Cooperative antigen transfer (CAT) is recently discovered phenomenon which substantially contributes to the establishment ofT cellcentral tolerance.
Thymus represents an origin of T cell development and its duty is to select functional but also safe T cells which will not plunder self tissues. Self-harmful T cells, further reffered asautoreactive T cells, originate in the thymus because of the stochastic process calledV(D)J recombination which conducts the generation ofT cell receptors (TCRs) and enables their boundless variability. Two processes of central tolerance take place in thymic medulla, namelyclonal deletion (recessive tolerance) andT Regulatory cells selection (dominant tolerance) which force autoreactive T cells toapoptosis or skew them into supressorT regulatory cells (TRegs), respectively, in order to protect body against manifestations ofautoimmunity.
mTECs are not only capable to present TRAs as efficientAntigen-presenting cells. They are also potent in production of these TRAs via unique process calledpromiscuous gene expression (PGE)[2] and might serve as their reservoir.
mTECs as APCs reveal some drawbacks on population level. Their numbers in thymic medulla reach only 100 000 per 2 week old thymus.[3] Furthermore, average lifespan of mTECs doesn´t exceed 2-3 days,[4] probably due to only known PGE activatorAutoimmune regulator (Aire),[5] which requires for its proper function generation ofDNA double strand breaks.[6] And last but not least, each TRA is expressed only by 1-3% of mTEC population.[7] These facts decrease the chance of efficient recessive or dominant tolerance.
Unidirectional spreading of mTEC-derived TRAs onto additional APCs via CAT increases the probability of encounter between potential autoreactive T cell and its corresponding TRA and therefore enhances processes of central tolerance. Furthermore, CAT enables TRA processing and presentation by different cellular microenvironments.
Despite relevance of CAT, seminal study was published, showing mTECs to form fully established central tolerance without support of additional APCs.[8]
First article which touches CAT was published in 2004. Experiments from this study reveal that clonal deletion of autoreactiveCD4+ T cells, apart fromCD8+ T cells, requires indirect presentation of TRAs bybone marrow (BM) derived APCs. Direct presentation of TRAs by mTECs was shown to be insufficient in this case.[9] Requirement of indirect presentation of some mTEC-derived TRAs in the case of recessive tolerance was percieved also by additional studies which both firstly demonstrated CAT as an instrument that enables this process.[10][11] Need of TRA indirect presentation is probably closely related with above mentioned "processing of TRAs by different microenvironments".
N.B.: BM derived APCs don´t express TRAs, this process is uniquely dedicated to mTECs. Exception is represented by thymic B cells which were shown to express TRAs and Aire.[12][13]
Systemic ablation of dendritic cells (DCs) was shown to cause fatal manifestations of autoimmunity[14] which points to their importance in central tolerance. Indeed, as mTECs represent exclusivedonors of TRAs, experiments with first CAT mouse models discovered thymicdendritic cells (DCs) to be so far the only knownTRAs acceptors involved in CAT.[10][11] Indispensability of DCs for the establishment of central tolerance was further verified by recent analysis, which revealed that DCs mediate both recessive and dominant tolerance, with preference for the latter, via presentation of more common TRAs.[15][16]
The most efficient subset in TRA presentation and both modes of central tolerance was found to be CD8α+thymic-derived DCs (tDCs).[15] This subset was also shown to express XCR1 and to be attracted by mTECs via XCL1 chemokine expression.[17] tDCs rise intrathymically and constitute approximately half of thymic DCs population.[18]
Sirpα+migratory DCs (mDCs) form second subset of thymic DCs.[19] They rise extrathymically, and were shown to present self antigens, especially blood-borne antigens, in the thymus, which they acquire in the periphery.[20] They were also shown to be more efficient in T regulatory cells selection than clonal deletion.[18]
The last abundant subset of thymic DCs is represented by B220+plasmacytoid DCs (pDCs)[19] which also rise extrathymically and transfer peripheral antigens from the periphery to the thymus to mediate selection processes.[21]
All these thymic DC subsets were shown to participate in CAT. Nevertheless, only tDCs and mDCs were observed to utilize transfered TRAs for indirect presentation which led to processes of central tolerance.[22]
The unambigous mechanism of CAT is still unknown. However, there are three possible ways:I.acquisition of mTEC apoptotic bodies, which could possibly be related with low mTEC lifespan[4]II.acquisition of exosomes andIII.acquisition viatrogocytosis, how CAT can be mediated.[10][11][22]
There is also an evidence, that CAT and therefore indirect presentation by thymic DCs are regulated by PGE activator Aire.[23]
