293:. This is a control step, in which the progenitor needs to receive positive signal from the pre-TCR to survive. They further need signal from CXCR4 (ligand is CXCL12) which does not serve here to direct migration but as a survival signal along with Notch signalling. Therefore, the β-selection step controls whether the TCRβ chain is properly formed and functional. It can be also understood as a positive selection specific only for the TCRβ chain (TCRα chain is not yet formed) but control for self-reactivity is not included in this step and comes later, especially in the medullary section. The cells that do not create functional γδTCR or pre-TCR or do not successfully pass through β-selection are removed by apoptosis. The cells that successfully pass the β-selection continue their development into DN4 stage, stop the expression of CD25 becoming CD44- CD25- and begin migration inside thymic cortex. It is, again, not completely clear what drives the migration. Probably, the receptors CXCR4 and CXCR9 on the DN4 cells drive the migration along gradients of chemokines CXCL12 and CCL25, although other models of migration to the cortex were established mainly based on movement dynamics of cells due to their extensive proliferation or fluid currents in the thymus without direct involvement of chemokine-driven migration. The DN4 cells subsequently begin the expression of CD8 and CD4 coreceptors becoming CD8+ CD4+ DP cells (DP means double positive because they express both the coreceptors). Once in the thymic cortex, the DP cells finalize the rearrangement of TCRα chain, which results in production of complete αβTCR complex, which marks the cells ready to enter the positive selection, which takes place in the thymic cortex.
289:(recombinases of the V(D)J recombination of T or B cell receptors). Therefore, it is the DN3 stage at which the T cell precursors start to build their TCRs. It is also at this stage when the precursors decide whether they become αβ or γδ T cell. There are two possible models of how this decision step is made. The first possibility is that the cell fate is simply determined during the development of the precursor by the commitment similar to the development of other cell lineages. Therefore, some T cell precursors commit to γδ T cell and therefore in this step recombine γδTCR and some commit to αβ T cell and similarly recombine αβTCR. The other and generally more accepted model is that the commitment is determined during the TCR rearrangement and formation. Since the V(D)J recombination is step-by-step process, the precursors firstly recombine their genes to produce γδTCR. At the moment, the strength of signal that is produced by the newly formed TCR decides. If the γδTCR is properly formed and receives strong signal by interacting with the ligands present in the thymus, then the precursor continue its development into γδ T cell through specific selection processes. If the T cell precursor receives only weak signal, then the γδTCR formation is scratched and the recombination towards αβTCR starts. Those precursors firstly recombine TCRβ chain and combine it with invariant TCRα (substitute chain) and in previous stages formed CD3 complex to create so-called pre-TCR. With this premature TCR, they enter process called
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also do not express CD3 complex). The DN stages can be distinguished by the expression of surface markers CD44 and CD25, with the DN1 cells being CD44+ CD25-. Similarly to the TSPs, the DN1 cells are still capable of generating other cell types aside from T cells, such as B cells, NK cells, DCs and macrophages (lymphoid and myeloid lineage). But, due to the Notch signalling, they start to committing towards T cell lineage by expression of transcription factors (TFs) such as GATA3 and TCF1. Subsequently, the DN1 cells differentiate into DN2 cells, that are CD44+ and CD25+. The DN2 stage can be further divided into two substages DN2a and DN2b. The transition from the earlier DN2a substage to the later DN2b is also called commitement, because it is at this moment when the T cell precursor finally and completely lose their ability to generate other cell lineages and from that moment they can (even in vitro) only differentiate into T cells. After the commitement, at the DN2b substage, the precursors also start to produce CD3 complex (signalling component of the future TCR receptor complex). Next, the precursors continue their differentiation into DN3 phase in which they are CD44- CD25+. At this stage, the cells finally arrive to the subcapsular zone of the thymus, further proliferate and most importantly, start to express
246:“ because they have the ability of self-renewal (generating new HSCs) and also have the potential to differentiate into all blood cell types. The direct descendants of HSCs are the more mature multipotent progenitors (MPPs) that highly proliferate, can differentiate into all blood cell types but are not capable of self-renewal (do not have the ability to indefinitely generate new MPPs and therefore HSCs are needed for generation of new MPPs). Some of the MPPs further upregulate expression of FLT3 (becoming CD150- FLT3high) and start to upregulate genes specific for lymphoid lineage (for example Rag1) (but remain Lin-). These progenitors (still belong to the LSK cells) consist of two similar populations termed lymphoid-primed MPPs (LMPPs) and early lymphoid progenitors (ELPs). The LMPPs/ELPs subsequently give rise to common lymphoid progenitors (CLPs). These cells (FLT3high LIN- KITlow) do not belong to LSK pool, are more mature and more prone towards the lymphoid lineage, meaning that under normal circumstances they will ultimately give rise to T or B cells or other lymphocytes (
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progenitors, only the LMPPs/ELPs and CLPs express chemokine receptors CCR7 and CCR9 that enable them to enter the thymus. The thymic endothelium express chemokines CCL19 and CCL21, which are ligands for CCR7 and CCL25 which is a ligand for CCR9. The final part of thymic entry is not yet fully understood. Suggested model is that receptor sensing of chemokines by the progenitors activates their integrins (suggested integrins are VLA-4 and LFA-1) which engage with ligands on the endothelium. This interaction stops the rolling, leads to cellular arrest and finally to transmigration along the chemokine gradient inside thymus. Therefore, all the progenitors will be rolling on the thymic endothelium, but only the LMPPs/ELPs and CLPs will enter the thymus because only they have the proper receptor equipement to do so. The mechanism is highly similar to the
115:, enzymes necessary for somatic recombination, has been linked to development of immune cytopenias in which antibodies are produced against the patient's blood cells. Due to the nature of a random receptor recombination, there will be some BCRs and TCRs produced that recognize self antigens as foreign. This is problematic, since these B and T cells would, if activated, mount an immune response against self if not killed or inactivated by central tolerance mechanisms. Therefore, without central tolerance, the immune system could attack self, which is not sustainable and could result in an autoimmune disorder.
242:(BM). Population of the earliest hematopoietic progenitors do not bear markers of differentiated cells (for that they are called Lin- „lineage negative“) but express molecules such as SCA1 (stem cell antigen) and KIT (receptor for stem cell factor SCF). Based on these markers the cells are called LSKs (Lineage-SCA1-KIT). This population can be further divided, based on expression of markers such as CD150 and FMS-related tyrosine kinase 3 (FLT3), into CD150+ FLT3-hematopoietic stem cells (HSCs) and CD150- FLT3low multipotent progenitors (MPPs). The HSCs are „true
210:" which tests the thymocytes for self-reactivity. The cells that are strongly self-reactive (and therefore prone to attacking the host cells) are removed by apoptosis. Thymocytes that are still self-reactive, but only slightly develop into T regulatory (Treg) cells. Thymocytes that are not self-reactive become mature naïve T cells. Both the Treg and mature naïve T cells subsequently migrate to the secondary lymphoid organs. The negative selection has its name because it selects for survival only those thymocytes whose TCRs
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ultimately become only capable to create T cells but this comes at the later stages of the differentiation. At the stage of TSPs, the progenitors still retain the capacity to create both lymphoid and myeloid cells. Given their capability to generate other cell lineages (mainly in vitro) it is even debated that they can physiologically, at least partially contribute to generation of other cell types, present in the thymus, mainly plasmacytoid dendritic cells (pDCs). But this has not yet been clearly proven.
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is that they migrate along chemokine gradients, using CXCR4, CCR7 and CCR9 receptors but the migration can be also driven only by interactions of integrins and other cells and ECM (extra-cellular matrix) without direct involvement of chemokines. As they migrate towards the subcapsular zone, the TSPs further continue in their differentiation, which is driven mainly by the thymic microenvironment. Out of many signals the TSPs and other subsequent precursors receive from the microenvironment, the
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146:(Treg cells) are directly reactive towards self-antigens (although their self-reactivity is not very strong) and use this autoreactivity to regulate immune reactions by suppressing immune system when it should not be active. Importantly, lymphocytes can only develop tolerance towards antigens that are present in the bone marrow (for B cells) and thymus (for T cells).
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From the moment LMPPs/ETPs and CLPs enter the thymus in the corticomedullary junction, they are referred to as thymus settling progenitors (TSPs). The TSPs highly proliferate and start to migrate to the subcapsullar zone of the thymus. It is not celar what signals drive the migration. One possibility
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The first use of central tolerance was by Ray Owen in 1945 when he noticed that dizygotic twin cattle did not produce antibodies when one of the twins was injected with the other's blood. His findings were confirmed by later experiments by Hasek and
Billingham. The results were explained by Burnet's
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Central tolerance is essential to proper immune cell functioning because it helps ensure that mature B cells and T cells do not recognize self-antigens as foreign microbes. More specifically, central tolerance is necessary because T cell receptors (TCRs) and B cell receptors (BCRs) are made by cells
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In the next step, the TSPs give rise to early thymic precursors (ETPs), also called as double negative 1 (DN1) cells. The term „double negative“ refers to the fact that at this stage the precursors do not express CD4 nor CD8 coreceptors (sometimes they are even termed „triple negative“ because they
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Progenitors from bone marrow (BM), even the HSCs, have the ability to randomly exit the BM to the bloodstream and thus can be readily detected there. Therefore, after being generated, the T cell progenitors exit the BM and are randomly carried by blood throughout the body. At the moment they reach
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is especially important to drive their differentiation fate. The precursors express Notch1 receptor which is activated by ligands present in the thymic tissue. The subsequent activation of Notch pathway leads to gradual loss of the progenitors capability to generate other cell lineages and they
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occurs during recombination and serves to further increase the diversity of BCRs and TCRs. The production of random TCRs and BCRs is an important method of defense against microbes due to their high mutation rate. This process also plays an important role in promoting the survival of a species,
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and some of the developing T cell clones produce TCR that is completely unfunctional (unable to bind peptide-MHC complexes) and some produce TCR that is self-reactive and could therefore promote autoimmunity. These "problematic" clones are therefore removed from the pool of T cells by specific
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cortico-medullary junction, they start slowing down and rolling on the endothelium, because all the progenitors, including LSK cells, express on their surface glycoprotein PSGL1, which is a ligand for P-selectin, expressed on the thymic endothelium. But out of all the aforementioned T cell
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The result of central tolerance is a population of lymphocytes that do not mount immune response towards self-antigens. These cells use their TCR or BCR specificity to recognize foreign antigens, in order to play their specific roles in immune reaction against those antigens.
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Two other terms - recesive and dominant tolerance are also important regarding the T cell central tolerance. Both the terms refer to two possible ways of tolerance establishment towards particular antigen (typically self antigen). The
447:: the self-reactive B cell changes specificity by rearranging genes and develops a new BCR that does not respond to self. This process gives the B cell a chance for editing the BCR before it is signaled to apoptose or becomes anergic.
474:. This leads to a lack of expression of peripheral antigens in the thymus, and hence a lack of negative selection towards key peripheral proteins such as insulin. Multiple autoimmune symptoms result.
226:" means that the T cell clones specific for the antigen are deviated into Treg cells and therefore suppress the immune response against the antigen (Treg selection during the negative selection).
850:
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. (May 2006). "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells".
222:" means that the antigen is tolerated via deletion of those T cells that would facilitate immune response against the antigen (deletion of autoreactive cells in negative selection). The "
127:
In this way, the mechanisms of central tolerance ensure that lymphocytes that would recognise self-antigens in a way that could endanger the host, are not released into the periphery.
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because there will be a variety of receptor arrangements within a species – this enables a very high chance of at least one member of the species having receptors for a novel antigen.
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is distinct from central tolerance in that it occurs once developing immune cells exit primary lymphoid organs (the thymus and bone-marrow), prior to their export into the periphery.
1588:
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. (November 2002). "Projection of an immunological self shadow within the thymus by the aire protein".
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complex, it does not receive survival signals, so it dies via apoptosis. T cell receptors with sufficient affinity for peptide-MHC complexes are selected for survival.
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The T cells that do not bind self, but do recognize antigen/MHC complexes, and are either CD4+ or CD8+, migrate to secondary lymphoid organs as mature naïve T cells.
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It is of note that T cells, despite tolerance mechanisms, are at least to some extent self-reactive. TCR of conventional T cells must be able to recognize parts of
250:). But since they are only progenitors, their cell fate is not strictly predetermined and they still have the ability to differentiate into other lineages.
103:, is important because it increases the receptor diversity which increases the likelihood that B cells and T cells will have receptors for novel antigens.
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are another type of T cell that mature in the thymus. Selection of T reg cells occurs in the thymic medulla and is accompanied by the transcription of
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While the process of somatic recombination is essential to a successful immune defense, it can lead to autoreactivity. For example, lack of functional
17:
331:, T cells are tested for their affinity to self. If they bind a self peptide, then they are signaled to apoptose (process of clonal deletion).
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Zlotoff, Daniel A.; Sambandam, Arivazhagan; Logan, Theodore D.; Bell, J. Jeremiah; Schwarz, Benjamin A.; Bhandoola, Avinash (11 March 2010).
1237:
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Kim JM, Rasmussen JP, Rudensky AY (February 2007). "Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice".
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Positive selection occurs in the thymic cortex with the help of thymic epithelial cells that contain surface MHC I and MHC II molecules.
1639:
Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (April 2003). "Aire regulates negative selection of organ-specific T cells".
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903:"Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns"
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exists as a secondary mechanism to ensure that T and B cells are not self-reactive once they leave primary lymphoid organs.
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952:"Formation of the Intrathymic Dendritic Cell Pool Requires CCL21-Mediated Recruitment of CCR7 Progenitors to the Thymus"
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364:. T reg cells are important for regulating autoimmunity by suppressing the immune system when it should not be active.
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hypothesis. Burnet and
Medawar won the Nobel Prize in 1960 for their work in explaining how immune tolerance works.
2176:
1188:"The long road to the thymus: the generation, mobilization, and circulation of T-cell progenitors in mouse and man"
300:, T cells are checked for their ability to bind peptide-MHC complexes with affinity. If the T cell cannot bind the
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Properly functioning B cell receptors recognize non-self antigen, or pathogen-associated molecular proteins (
178:" the thymocytes are tested, ehether their TCR works properly and those with unfunctional TCR are removed by
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play important roles in the expression of self tissue antigens on the thymic epithelial cells in the thymus.
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in case of CD4+ T cells) to create proper interaction with antigen-presenting cell. Furthermore, TCRs of
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1432:"Single-cell insights into the hematopoietic generation of T-lymphocyte precursors in mouse and human"
195:" (or lineage commitment) takes place. In this process the thymocytes whose TCR recognize with MHCI (
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999:
Palmer E (May 2003). "Negative selection--clearing out the bad apples from the T-cell repertoire".
214:(or interact only slightly) with peptide-MHC complexes on antigen presenting cells in the thymus.
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Cosway EJ, Ohigashi I, Schauble K, Parnell SM, Jenkinson WE, Luther S, et al. (July 2018).
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The thymic epithelial cells display self antigen to the T cells to test their affinity for self.
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to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the
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182:. The mechanism has its name because it selects for survival only those thymocytes whose TCRs
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Immature B cells in the bone marrow undergo negative selection when they bind self peptides.
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Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, et al. (February 2016).
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where they continue their development. During this development, the thymocytes perform the
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This figure depicts the process of positive selection and MHC restriction for T cells.
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Negative selection occurs in the cortico-medullary junction and in the thymic medulla.
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79:. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
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765:"Central CD4 T cell tolerance: deletion versus regulatory T cell differentiation"
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Chen K, Wu W, Mathew D, Zhang Y, Browne SK, Rosen LB, et al. (March 2014).
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1238:"CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus"
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Liu YJ (May 2006). "A unified theory of central tolerance in the thymus".
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This figure depicts the process of B cell selection in the bone marrow.
266:, which is used by leukocytes to enter lymph nodes or inflamed tissues.
199:) molecules become CD4- CD8+ and thymocytes whose TCR recognize MHCII (
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with peptide-MHC complexes on antigen presenting cells in the thymus.
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Zlotoff, Daniel A.; Schwarz, Benjamin A.; Bhandoola, Avinash (2008).
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During the late stage of positive selection, another process called "
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Depending on whether the T cell binds MHC I or II, it will become a
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2015:
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1378:"An Overview of the Intrathymic Intricacies of T Cell Development"
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This figure depicts the process of negative selection for T cells.
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733:(5th ed.). New York, NY: Garland Science. pp. 533–546.
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64:
1780:"The curious case of the 1960 Nobel Prize to Burnet and Medawar"
1484:"Regulation of γδ T Cell Effector Diversification in the Thymus"
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Romagnani S (2006). "Immunological tolerance and autoimmunity".
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1739:"Immunological tolerance 50 years after the Burnet Nobel Prize"
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Genetic defects in central tolerance can lead to autoimmunity.
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Subsequently, the positively selected thymocytes go through "
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through random somatic rearrangement. This process, known as
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Elimination of autoreactive lymphocytes by the immune system
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Shah, Divya K.; Zúñiga-Pflücker, Juan Carlos (1 May 2014).
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1638:
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Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001).
639:
Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001).
67:. Lymphocyte maturation (and central tolerance) occurs in
1235:
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1300:"Hematopoietic progenitor migration to the adult thymus"
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Immunobiology 5: The Immune System in Health and
Disease
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Immunobiology 5: The Immune System in Health and
Disease
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Owen JA, Punt J, Stranford SA, Jones PP, Kuby J (2013).
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Ciofani, Maria; Zúñiga-Pflücker, Juan Carlos (2010).
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1687:"Historical overview of immunological tolerance"
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1298:Zlotoff, Daniel A.; Bhandoola, Avinash (2011).
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682:The Journal of Allergy and Clinical Immunology
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1543:"Determining γδ versus αß T cell development"
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468:Autoimmune Polyendocrinopathy Syndrome Type I
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763:Klein L, Robey EA, Hsieh CS (January 2019).
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1691:Cold Spring Harbor Perspectives in Biology
1482:Parker, Morgan E.; Ciofani, Maria (2020).
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1304:Annals of the New York Academy of Sciences
1129:Love, Paul E.; Bhandoola, Avinash (2011).
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727:"Chapter 13 – Self-tolerance and its loss"
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470:is caused by mutations in the human gene
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549:(7th ed.). New York: W.H. Freeman.
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82:Central tolerance is not perfect, so
402:Legend for T cell selection figures.
44:) is the process of eliminating any
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647:(5th ed.). New York: Garland.
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1111:
1071:"The thymus and central tolerance"
1069:Sprent J, Kishimoto H (May 2001).
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1077:. Series B, Biological Sciences.
238:T cell precursors originate from
236:Development of T cell progenitors
1324:10.1111/j.1749-6632.2010.05881.x
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154:T cell progenitors (also called
132:major histocompatibility complex
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595:Internal and Emergency Medicine
18:Negative selection (immunology)
2172:Immunoglobulin class switching
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718:
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1:
1778:Silverstein AM (March 2016).
1430:Rothenberg, Ellen V. (2021).
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257:postcapillary venules in the
1448:10.1016/j.exphem.2020.12.005
1254:10.1182/blood-2009-08-237784
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55:that are autoreactive, i.e.
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1743:Immunology and Cell Biology
1703:10.1101/cshperspect.a006908
1192:Seminars in Immunopathology
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454:(a state of non-reactivity)
337:Transcriptional regulators
138:in case of CD8+ T cells or
93:
10:
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2001:Polyclonal B cell response
1685:Schwartz RH (April 2012).
1547:Nature Reviews. Immunology
1001:Nature Reviews. Immunology
772:Nature Reviews. Immunology
694:10.1016/j.jaci.2013.11.038
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254:Migration into the thymus
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1966:
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1737:Liston A (January 2011).
1382:The Journal of Immunology
1204:10.1007/s00281-008-0133-4
1135:Nature Reviews Immunology
784:10.1038/s41577-018-0083-6
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230:Steps of T cell tolerance
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1501:10.3389/fimmu.2020.00042
1394:10.4049/jimmunol.1302259
968:10.4049/jimmunol.1800348
826:10.1016/j.it.2006.03.004
270:Early thymic development
244:hematopoietic stem cells
162:and then migrate to the
1610:10.1126/science.1075958
1488:Frontiers in Immunology
1436:Experimental Hematology
69:primary lymphoid organs
2115:Tolerance in pregnancy
1857:adaptive immune system
1087:10.1098/rstb.2001.0846
419:
2150:Somatic hypermutation
1984:Polyclonal antibodies
1979:Monoclonal antibodies
956:Journal of Immunology
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319:T cell, respectively.
158:) are created in the
63:does not attack self
2167:Junctional diversity
1935:Antigen presentation
1756:10.1038/icb.2010.138
814:Trends in Immunology
508:Peripheral tolerance
203:) become CD4+ CD8-.
105:Junctional diversity
88:Peripheral tolerance
84:peripheral tolerance
2162:V(D)J recombination
2145:Affinity maturation
1897:Antigenic variation
1602:2002Sci...298.1395A
1596:(5597): 1395–1401.
1316:2011NYASA1217..122Z
872:10.1038/nature04753
864:2006Natur.441..235B
168:V(D)J recombination
101:V(D)J recombination
607:10.1007/bf02934736
420:
358:Regulatory T cells
329:negative selection
298:positive selection
224:dominant tolerance
220:recesive tolerance
208:negative selection
176:positive selection
144:regulatory T cells
42:negative selection
2261:
2260:
2189:
2188:
1939:professional APCs
1796:10.1111/imm.12558
1641:Nature Immunology
1248:(10): 1897–1905.
1081:(1409): 609–616.
1036:Nature Immunology
907:Nature Immunology
858:(7090): 235–238.
740:978-0-443-07098-3
654:978-0-8153-3642-6
556:978-1-4292-1919-8
441:(clonal deletion)
134:(MHC) molecules (
38:central tolerance
16:(Redirected from
2281:
2155:Clonal selection
2127:Immune privilege
2122:Immunodeficiency
2077:Cross-reactivity
2067:Hypersensitivity
1872:
1871:
1847:
1840:
1833:
1824:
1823:
1818:
1817:
1807:
1775:
1769:
1768:
1758:
1734:
1725:
1724:
1714:
1682:
1673:
1672:
1636:
1630:
1629:
1585:
1579:
1578:
1538:
1532:
1531:
1521:
1503:
1479:
1470:
1469:
1459:
1427:
1414:
1413:
1388:(9): 4017–4023.
1373:
1354:
1353:
1343:
1295:
1284:
1283:
1273:
1233:
1224:
1223:
1183:
1177:
1176:
1166:
1126:
1109:
1108:
1098:
1066:
1060:
1059:
1031:
1025:
1024:
996:
990:
989:
979:
947:
941:
940:
930:
898:
892:
891:
847:
838:
837:
809:
796:
795:
769:
760:
745:
744:
722:
716:
715:
705:
688:(3): 880–2.e10.
673:
667:
666:
646:
636:
627:
626:
590:
569:
568:
542:
486:clonal selection
459:Genetic diseases
445:Receptor editing
399:
387:
375:
275:Notch signalling
192:MHC restricition
21:
2289:
2288:
2284:
2283:
2282:
2280:
2279:
2278:
2264:
2263:
2262:
2257:
2231:
2185:
2131:
2110:Clonal deletion
2038:
2032:
1962:
1863:
1851:
1821:
1776:
1772:
1735:
1728:
1683:
1676:
1637:
1633:
1586:
1582:
1559:10.1038/nri2820
1539:
1535:
1480:
1473:
1428:
1417:
1374:
1357:
1296:
1287:
1234:
1227:
1184:
1180:
1147:10.1038/nri2989
1127:
1112:
1067:
1063:
1032:
1028:
1013:10.1038/nri1085
997:
993:
948:
944:
919:10.1038/ni.3327
899:
895:
848:
841:
810:
799:
767:
761:
748:
741:
723:
719:
674:
670:
655:
637:
630:
591:
572:
557:
547:Kuby immunology
543:
520:
516:
494:
481:
461:
412:
407:
406:
405:
404:
403:
400:
392:
391:
388:
380:
379:
376:
282:DN to DP stages
212:do not interact
174:First, during "
152:
121:
96:
40:(also known as
28:
23:
22:
15:
12:
11:
5:
2287:
2277:
2276:
2259:
2258:
2256:
2255:
2250:
2245:
2239:
2237:
2233:
2232:
2230:
2229:
2224:
2223:
2222:
2212:
2211:
2210:
2199:
2197:
2191:
2190:
2187:
2186:
2184:
2183:
2174:
2169:
2164:
2159:
2158:
2157:
2152:
2141:
2139:
2137:Immunogenetics
2133:
2132:
2130:
2129:
2124:
2119:
2118:
2117:
2112:
2107:
2102:
2097:
2085:
2084:
2082:Co-stimulation
2079:
2074:
2069:
2064:
2059:
2054:
2049:
2042:
2040:
2034:
2033:
2031:
2030:
2025:
2023:Immune complex
2019:
2018:
2013:
2008:
2003:
1998:
1997:
1996:
1991:
1986:
1981:
1970:
1968:
1964:
1963:
1961:
1960:
1955:
1950:
1945:
1943:Dendritic cell
1931:
1930:
1925:
1924:
1923:
1921:Conformational
1918:
1907:
1906:
1901:
1900:
1899:
1894:
1889:
1878:
1876:
1869:
1865:
1864:
1850:
1849:
1842:
1835:
1827:
1820:
1819:
1790:(3): 269–274.
1770:
1726:
1697:(4): a006908.
1674:
1647:(4): 350–354.
1631:
1580:
1553:(9): 657–663.
1533:
1471:
1415:
1355:
1310:(1): 122–138.
1285:
1225:
1198:(4): 371–382.
1178:
1141:(7): 469–477.
1110:
1061:
1048:10.1038/ni1428
1042:(2): 191–197.
1026:
1007:(5): 383–391.
991:
962:(2): 516–523.
942:
913:(2): 187–195.
893:
839:
820:(5): 215–221.
797:
746:
739:
717:
668:
653:
628:
601:(3): 187–196.
570:
555:
517:
515:
512:
511:
510:
505:
500:
493:
490:
480:
477:
476:
475:
460:
457:
456:
455:
448:
442:
411:
408:
401:
394:
393:
389:
382:
381:
377:
370:
369:
368:
367:
366:
355:
354:
351:
350:
349:
346:
335:
325:
324:
323:
320:
294:
279:
267:
264:transmigration
251:
151:
148:
120:
117:
95:
92:
26:
9:
6:
4:
3:
2:
2286:
2275:
2272:
2271:
2269:
2254:
2251:
2249:
2246:
2244:
2241:
2240:
2238:
2234:
2228:
2225:
2221:
2218:
2217:
2216:
2213:
2209:
2206:
2205:
2204:
2201:
2200:
2198:
2196:
2192:
2182:
2178:
2175:
2173:
2170:
2168:
2165:
2163:
2160:
2156:
2153:
2151:
2148:
2147:
2146:
2143:
2142:
2140:
2138:
2134:
2128:
2125:
2123:
2120:
2116:
2113:
2111:
2108:
2106:
2105:Clonal anergy
2103:
2101:
2098:
2096:
2093:
2092:
2091:
2087:
2086:
2083:
2080:
2078:
2075:
2073:
2070:
2068:
2065:
2063:
2060:
2058:
2055:
2053:
2050:
2048:
2044:
2043:
2041:
2035:
2029:
2026:
2024:
2021:
2020:
2017:
2014:
2012:
2009:
2007:
2004:
2002:
1999:
1995:
1994:Microantibody
1992:
1990:
1987:
1985:
1982:
1980:
1977:
1976:
1975:
1972:
1971:
1969:
1965:
1959:
1956:
1954:
1951:
1949:
1946:
1944:
1940:
1936:
1933:
1932:
1929:
1926:
1922:
1919:
1917:
1914:
1913:
1912:
1909:
1908:
1905:
1902:
1898:
1895:
1893:
1890:
1888:
1885:
1884:
1883:
1880:
1879:
1877:
1873:
1870:
1866:
1862:
1858:
1855:
1848:
1843:
1841:
1836:
1834:
1829:
1828:
1825:
1815:
1811:
1806:
1801:
1797:
1793:
1789:
1785:
1781:
1774:
1766:
1762:
1757:
1752:
1748:
1744:
1740:
1733:
1731:
1722:
1718:
1713:
1708:
1704:
1700:
1696:
1692:
1688:
1681:
1679:
1670:
1666:
1662:
1658:
1654:
1653:10.1038/ni906
1650:
1646:
1642:
1635:
1627:
1623:
1619:
1615:
1611:
1607:
1603:
1599:
1595:
1591:
1584:
1576:
1572:
1568:
1564:
1560:
1556:
1552:
1548:
1544:
1537:
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1520:
1515:
1511:
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1485:
1478:
1476:
1467:
1463:
1458:
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1445:
1441:
1437:
1433:
1426:
1424:
1422:
1420:
1411:
1407:
1403:
1399:
1395:
1391:
1387:
1383:
1379:
1372:
1370:
1368:
1366:
1364:
1362:
1360:
1351:
1347:
1342:
1337:
1333:
1329:
1325:
1321:
1317:
1313:
1309:
1305:
1301:
1294:
1292:
1290:
1281:
1277:
1272:
1267:
1263:
1259:
1255:
1251:
1247:
1243:
1239:
1232:
1230:
1221:
1217:
1213:
1209:
1205:
1201:
1197:
1193:
1189:
1182:
1174:
1170:
1165:
1160:
1156:
1152:
1148:
1144:
1140:
1136:
1132:
1125:
1123:
1121:
1119:
1117:
1115:
1106:
1102:
1097:
1092:
1088:
1084:
1080:
1076:
1072:
1065:
1057:
1053:
1049:
1045:
1041:
1037:
1030:
1022:
1018:
1014:
1010:
1006:
1002:
995:
987:
983:
978:
973:
969:
965:
961:
957:
953:
946:
938:
934:
929:
924:
920:
916:
912:
908:
904:
897:
889:
885:
881:
877:
873:
869:
865:
861:
857:
853:
846:
844:
835:
831:
827:
823:
819:
815:
808:
806:
804:
802:
793:
789:
785:
781:
777:
773:
766:
759:
757:
755:
753:
751:
742:
736:
732:
728:
721:
713:
709:
704:
699:
695:
691:
687:
683:
679:
672:
664:
660:
656:
650:
645:
644:
635:
633:
624:
620:
616:
612:
608:
604:
600:
596:
589:
587:
585:
583:
581:
579:
577:
575:
566:
562:
558:
552:
548:
541:
539:
537:
535:
533:
531:
529:
527:
525:
523:
518:
509:
506:
504:
501:
499:
496:
495:
489:
487:
473:
469:
466:
465:
464:
453:
450:Induction of
449:
446:
443:
440:
437:
436:
435:
434:
430:
428:
423:
416:
398:
386:
374:
365:
363:
359:
352:
347:
344:
340:
336:
333:
332:
330:
326:
321:
318:
314:
310:
309:
307:
303:
299:
295:
292:
288:
287:Rag1 and Rag2
283:
280:
276:
271:
268:
265:
260:
255:
252:
249:
245:
241:
237:
234:
233:
232:
231:
227:
225:
221:
215:
213:
209:
204:
202:
198:
194:
193:
187:
185:
181:
177:
172:
169:
165:
161:
157:
147:
145:
141:
137:
133:
128:
125:
116:
114:
109:
106:
102:
91:
89:
85:
80:
78:
74:
70:
66:
62:
61:immune system
58:
54:
53:B lymphocytes
50:
47:
43:
39:
35:
30:
19:
2094:
2072:Inflammation
2057:Alloimmunity
2052:Autoimmunity
2037:Immunity vs.
1989:Autoantibody
1887:Superantigen
1787:
1783:
1773:
1749:(1): 14–15.
1746:
1742:
1694:
1690:
1644:
1640:
1634:
1593:
1589:
1583:
1550:
1546:
1536:
1491:
1487:
1439:
1435:
1385:
1381:
1307:
1303:
1245:
1241:
1195:
1191:
1181:
1138:
1134:
1078:
1074:
1064:
1039:
1035:
1029:
1004:
1000:
994:
959:
955:
945:
910:
906:
896:
855:
851:
817:
813:
775:
771:
730:
720:
685:
681:
671:
642:
598:
594:
546:
498:Autoimmunity
482:
462:
432:
431:
424:
421:
356:
328:
306:MHC class II
297:
290:
281:
269:
253:
235:
229:
228:
223:
219:
216:
211:
207:
205:
201:MHC class II
190:
188:
183:
175:
173:
171:mechanisms.
153:
140:MHC class II
129:
126:
122:
110:
97:
81:
71:such as the
45:
41:
37:
31:
29:
2195:Lymphocytes
1854:Lymphocytic
778:(1): 7–18.
302:MHC class I
291:β-selection
240:bone marrow
197:MHC class I
184:do interact
160:bone marrow
136:MHC class I
73:bone marrow
2274:Immunology
2236:Substances
2100:Peripheral
2088:Inaction:
1967:Antibodies
1948:Macrophage
1861:complement
1784:Immunology
514:References
503:Immunology
156:thymocytes
46:developing
34:immunology
2253:Cytolysin
2243:Cytokines
2090:Tolerance
2039:tolerance
1958:Immunogen
1567:1474-1741
1510:1664-3224
1402:0022-1767
1332:0077-8923
1262:0006-4971
1212:1863-2297
1155:1474-1733
565:820117219
439:Apoptosis
180:apoptosis
119:Mechanism
2268:Category
2203:Cellular
2047:Immunity
2045:Action:
2028:Paratope
2016:Idiotype
2006:Allotype
1974:Antibody
1928:Mimotope
1892:Allergen
1875:Antigens
1868:Lymphoid
1814:26790994
1765:21209621
1721:22395097
1661:12612579
1626:13989491
1618:12376594
1575:20725107
1528:32038664
1466:33454362
1442:: 1–12.
1410:24748636
1350:21251013
1280:19965655
1220:18925398
1173:21701522
1105:11375064
1056:17136045
1021:12766760
986:29784760
937:26726812
880:16648838
834:16580260
792:30420705
712:24472623
663:45708106
623:27585046
615:17120464
492:See also
248:NK cells
94:Function
75:and the
65:peptides
57:reactive
2248:Opsonin
2227:NK cell
2215:Humoral
2095:Central
2062:Allergy
2011:Isotype
1911:Epitope
1882:Antigen
1805:4754613
1712:3312674
1669:4561402
1598:Bibcode
1590:Science
1519:6992645
1457:8018899
1341:3076003
1312:Bibcode
1271:2837318
1164:3710714
1096:1088448
977:6036229
928:4718891
888:4391497
860:Bibcode
703:4107635
479:History
327:During
296:During
2220:B cell
2208:T cell
1953:B cell
1916:Linear
1904:Hapten
1812:
1802:
1763:
1719:
1709:
1667:
1659:
1624:
1616:
1573:
1565:
1526:
1516:
1508:
1494:: 42.
1464:
1454:
1408:
1400:
1348:
1338:
1330:
1278:
1268:
1260:
1218:
1210:
1171:
1161:
1153:
1103:
1093:
1054:
1019:
984:
974:
935:
925:
886:
878:
852:Nature
832:
790:
737:
710:
700:
661:
651:
621:
613:
563:
553:
452:anergy
410:B cell
259:thymic
164:thymus
150:T cell
113:RAG1/2
77:thymus
1665:S2CID
1622:S2CID
1242:Blood
884:S2CID
768:(PDF)
619:S2CID
427:PAMPs
362:FOXP3
343:Fezf2
1859:and
1810:PMID
1761:PMID
1717:PMID
1657:PMID
1614:PMID
1571:PMID
1563:ISSN
1524:PMID
1506:ISSN
1462:PMID
1406:PMID
1398:ISSN
1346:PMID
1328:ISSN
1308:1217
1276:PMID
1258:ISSN
1216:PMID
1208:ISSN
1169:PMID
1151:ISSN
1101:PMID
1052:PMID
1017:PMID
982:PMID
933:PMID
876:PMID
830:PMID
788:PMID
735:ISBN
708:PMID
659:OCLC
649:ISBN
611:PMID
561:OCLC
551:ISBN
472:AIRE
341:and
339:AIRE
317:CD4+
313:CD8+
2181:HLA
2177:MHC
1800:PMC
1792:doi
1788:147
1751:doi
1707:PMC
1699:doi
1649:doi
1606:doi
1594:298
1555:doi
1514:PMC
1496:doi
1452:PMC
1444:doi
1390:doi
1386:192
1336:PMC
1320:doi
1266:PMC
1250:doi
1246:115
1200:doi
1159:PMC
1143:doi
1091:PMC
1083:doi
1079:356
1044:doi
1009:doi
972:PMC
964:doi
960:201
923:PMC
915:doi
868:doi
856:441
822:doi
780:doi
698:PMC
690:doi
686:133
603:doi
429:).
315:or
304:or
51:or
32:In
2270::
1941::
1808:.
1798:.
1786:.
1782:.
1759:.
1747:89
1745:.
1741:.
1729:^
1715:.
1705:.
1693:.
1689:.
1677:^
1663:.
1655:.
1643:.
1620:.
1612:.
1604:.
1592:.
1569:.
1561:.
1551:10
1549:.
1545:.
1522:.
1512:.
1504:.
1492:11
1490:.
1486:.
1474:^
1460:.
1450:.
1440:95
1438:.
1434:.
1418:^
1404:.
1396:.
1384:.
1380:.
1358:^
1344:.
1334:.
1326:.
1318:.
1306:.
1302:.
1288:^
1274:.
1264:.
1256:.
1244:.
1240:.
1228:^
1214:.
1206:.
1196:30
1194:.
1190:.
1167:.
1157:.
1149:.
1139:11
1137:.
1133:.
1113:^
1099:.
1089:.
1073:.
1050:.
1038:.
1015:.
1003:.
980:.
970:.
958:.
954:.
931:.
921:.
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