The developmental diversion of thymocytes

I like reports that make me learn something new and appreciate novel developments leading to more integral view of immunological concepts. My understanding of the thymic central tolerance process was that thymocytes receiving strong signals from tissue antigens through TCR undergo invariably the clonal deletion. But it looks like the clonal deletion of cells that can develop into potentially autoreactive T lymphocytes is not the only way which exists for such population in the thymus. I have read the paper that suggests that there may be actually two outcomes for thymocytes with self-reactive TCR – first is the clonal deletion whereas second the developmental diversion.

The link: http://www.nature.com/ni/journal/v13/n6/abs/ni.2292.html

What is the developmental diversion, though? According to authors it is a process that happens when a thymocyte gets the signal through its autoreactive TCR but is not able to receive the costimulation with CD28 molecule. In such case it can enter a pool of DN cells (double negative for CD4 and CD8) and turn up in the intestinal epithelium where it re-expresses CD8 (in its αα form). Cells derived from the developmental diversion are anergic and when the clonal deletion is impaired (as for example in CD28 knockout mice) the efficiency of central tolerance is not reduced because autoreactive thymocytes have an substitute pathway that sequesters them from harmful and self-reactive mature population.

How the the developmental diversion was detected? The publication contains a lot of data, so I will focus on most crucial evidence. The initial observation made by investigators was that CD28 knockout mice (and also B7 double knockout with no CD80 and CD86 which are CD28 ligands) has unusually numerous population of DN thymocytes that express TCRαβ. In normal mice DN thymocytes are in their majority TCRαβ-negative. The DN population from mice deleted for CD28 contains also the similar proportion of autoreactive TCRs as pre-selection DP (double positive) thymocytes but mature C4 or CD8 T cells from the same strain are mostly deprived of self-reactive rearrangement. Therefore authors conclude that the clonal deletion of autoreactive thymocytes requires CD28 costimulation and in its absence such cells are diverted into the alternative developmental way.

Investigators follow this phenomenon by studying at what exact stage of thymocyte development the diversion may occur and what happens with diverted thymocytes once they leave the thymus (they end up in the intestinal epithelium as already has been remarked). The most interesting thing, however, is that the developmental diversion seems to take place in normal mice as well as TCRαβ+CD8ααintraepithelial lymphocytes from the wild type strain are enriched for autoreactive specificities. I definitely need to start following this story.

Pobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, Park JH, & Singer A (2012). Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nature immunology, 13 (6), 569-78 PMID: 22544394

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The hidden nature of TCR

The adaptive immune system uses the anticipatory receptor strategy as a mean to detect foreign antigens. Despite that these anticipatory receptors are arranged by similar gene recombination mechanisms in two main lymphocyte types they are not alike in the way they operate. Receptors on T cells are MHC restricted which means that they can recognize exclusively pre-processed linear peptides bound to major histocompatibility complexes. In contrast receptors on B lymphocytes bind to antigens that remain in their native conformation. The recent publication providing data on the very basics of MHC restriction can teach us more about the hidden nature of TCR.

The link: http://www.cell.com/immunity/abstract/S1074-7613(11)00520-6

The report aims to distinguish whether MHC restriction stands as an intrinsic feature of TCR or could be imposed on T cells during their development. The molecular switch that underlies MHC restriction consists of TCR, CD4/CD8 co-receptors and Lck kinase. The role of co-receptors is to enforce that signaling from TCR occurs exclusively in the context of MHC binding. Co-receptors engage Lck kinase and make it available to TCR only when they are attached to MHC. Immature T cells start expressing CD4 and CD8 during their compulsory development stage in the thymus.

To make the distinction possible authors analyze binding specificities of TCRs that underwent the thymic selection in the joint absence of MHC and CD4/CD8 co-receptors. If the restriction feature was built-in to TCR structure than the sheer absence of MHC would yield TCRs unresponsive to any ligand. However, the lack of MHC and CD4/CD8 may as well allow the positive selection of receptors that recognize unprocessed antigens because the availability of Lck kinase to TCR would be independent of MHC binding. In such circumstances MHC restriction could be interpreted as enforced by the thymic selection. Authors show that this is indeed the case. Data indicate that TCRs educated without MHC and co-receptors bear the striking similarity to B cell receptors. They display affinity for antigens in the native conformation as well as bind their ligands as soluble proteins.

The main conclusion from this report has enticed me to do some musing about the evolutionary origin of lymphocyte. Obviously, vertebrate adaptive immune compartments with all their diversity, flexibility and mutual dependability did not start as we see them today – they had to be less complicated in the past. Could T cells originate from a B cell? I know that I’m looking like a fan of disproven recapitulation theory (which I’m not), but B cells seem like intuitive candidates for a primeval lymphocyte. They recognize antigen in the simpler way than T cells do – without the need for external support in the form of antigen presenting cell. But I am not entirely sure if you can extend these data so far. Probably you can’t.