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.

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