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get shortened url switch to legacy parser print export download as pdf printable version in other projects wikidata item appearance move to sidebar hide from wikipedia the free encyclopedia elimination of autoreactive lymphocytes by the immune system in immunology central tolerance also known as negative selection is the process of eliminating any developing t or b lymphocytes that are autoreactive i e reactive to the body itself 1 through elimination of autoreactive lymphocytes tolerance ensures that the immune system does not attack self peptides 2 lymphocyte maturation and central tolerance occurs in primary lymphoid organs such as the bone marrow and the thymus in mammals b cells mature in the bone marrow and t cells mature in the thymus 1 central tolerance is not perfect so peripheral tolerance exists as a secondary mechanism to ensure that t and b cells are not self reactive once they leave primary lymphoid organs 3 page needed peripheral tolerance 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 1 function edit 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 2 more specifically central tolerance is necessary because t cell receptors tcrs and b cell receptors bcrs are made by cells through random somatic rearrangement 1 this process known as v d j recombination is important because it increases the receptor diversity which increases the likelihood that b cells and t cells will have receptors for novel antigens 1 junctional diversity occurs during recombination and serves to further increase the diversity of bcrs and tcrs 1 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 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 1 while the process of somatic recombination is essential to a successful immune defense it can lead to autoreactivity for example lack of functional rag1 2 enzymes necessary for somatic recombination has been linked to development of immune cytopenias in which antibodies are produced against the patient s blood cells 4 due to the nature of a random receptor recombination there will be some bcrs and tcrs produced that recognize self antigens as foreign 2 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 5 page needed therefore without central tolerance the immune system could attack self which is not sustainable and could result in an autoimmune disorder 3 page needed mechanism edit 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 2 6 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 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 major histocompatibility complex mhc molecules mhc class i in case of cd8 t cells or mhc class ii in case of cd4 t cells to create proper interaction with antigen presenting cell furthermore tcrs of regulatory t cells 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 6 7 8 importantly lymphocytes can only develop tolerance towards antigens that are present in the bone marrow for b cells and thymus for t cells 9 t cell edit t cell progenitors also called thymocytes are created in the bone marrow and then migrate to the thymus where they continue their development 1 10 during this development the thymocytes perform the v d j recombination 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 11 2 these problematic clones are therefore removed from the pool of t cells by specific mechanisms first during positive selection the thymocytes are tested whether their tcr works properly and those with unfunctional tcr are removed by apoptosis 6 7 the mechanism has its name because it selects for survival only those thymocytes whose tcrs do interact with peptide mhc complexes on antigen presenting cells in the thymus during the late stage of positive selection another process called mhc restriction or lineage commitment takes place in this process the thymocytes whose tcr recognize mhci mhc class i molecules become cd4 cd8 and thymocytes whose tcr recognize mhcii mhc class ii become cd4 cd8 subsequently the positively selected thymocytes go through negative selection 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 6 7 the negative selection has its name because it selects for survival only those thymocytes whose tcrs do not interact or interact only slightly with peptide mhc complexes on antigen presenting cells in the thymus two other terms recessive 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 recessive tolerance 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 dominant tolerance 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 6 7 12 steps of t cell tolerance 2 13 development of t cell progenitors 14 15 16 t cell precursors originate from bone marrow 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 hematopoietic stem cells 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 nk cells but since they are only progenitors their cell fate is not strictly predetermined and they still have the ability to differentiate into other lineages migration into the thymus 14 16 17 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 postcapillary venules in the thymic 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 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 equipment to do so the mechanism is highly similar to the transmigration which is used by leukocytes to enter lymph nodes or inflamed tissues early thymic development 14 17 18 19 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 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 14 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 notch signalling 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 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 19 dn to dp stages 14 17 18 19 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 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 18 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 rag1 and rag2 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 18 19 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 18 20 21 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 β selection ...