On integrity in immunity during ontogeny or how thymic regulatory T cells work

Abstract

The Standard model of T cell recognition asserts that T cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus and that peripheral T cell repertoire has mild self-major histocompatibility complex (MHC) reactivity, known as MHC restriction of foreign antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope models suggest contradictory roles for complementarity-determining regions (CDRs) of the TCRs.Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR-MHC-conserved interaction. I suggest that double (CD4 + CD8 + )-positive (DP) developing thymocytes compete with their αβTCRs for binding to self-pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue-restricted antigens. The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal-centre B cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self-pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4 + Foxp3 + tTregs can be generated by mTECs via Aire-dependent and Aire-independent pathways, and additionally on thymic bone marrow-derived APCs including thymic Aire-expressing B cells. Thymic Tregs differ from the induced peripheral Tregs, which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes' competition for the highest binding to self-pMHC is the co-evolution of species-specific αβTCR V regions with MHC alleles.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

“…We accept the evidence for Dembic’s proposal of competitive high‐avidity TCR anti–self‐MHCI/II binding per se during ontogeny in the thymus. The review of that evidence by Dembic links it to subsequent migration of such positively selected thymic tTregs into the periphery where they act as immediate backup regulatory mechanisms during immune responses to non–self‐antigens – to maintain central tolerance against self T cell and B cell reactivity .…”

“…We advance here a model shown schematically in Figure for the co‐evolution of allele‐specific MHC recognition by the TCR confining the initial cellular events to somatic selection of thymic and peripheral Tregs. The model has grown quite naturally out of the recent proposal of Dembic and provides a mechanism to explain some previously long‐held assumptions, for example of Cohn et al, of MHC species‐specific allele recognition by the TCR. In the past, both the soma‐to‐germline feedback proposal and invocation of somatic hypermutation occurring in TCRs of mammalian T cells have been very controversial and thus inhibitory of ongoing research.…”

“…These specificities are the familiar background, often cross‐reactive, IgM ‘natural antibodies’ detected in normal healthy plasma in humans, mice and other vertebrates . We now extend the discussion on how thymic regulatory T (tTreg) cells work by Dembic and deal directly with the implications for understanding the mechanism of germline evolution of the allele‐specific TCR V segment repertoires.…”

“…In parallel to these processes, the normal peripheral T cell repertoire of CD4+ T helper and CD8+ T cytotoxic cells bear the less avid (milder) self‐MHC reactivity and behave as MHC restricted lineages responsive to foreign peptide antigens. Thus, conventional peripheral CD4+ and CD8+ expressed TCRs bind both a restrictive MHCI/II molecule with a peptide in the binding cleft (pMHC ligand), and thus allowing an immune activation signal to be transmitted into the T helper or T cytotoxic cells …”

“…Thus, conventional peripheral CD4+ and CD8+ expressed TCRs bind both a restrictive MHCI/II molecule with a peptide in the binding cleft (pMHC ligand), and thus allowing an immune activation signal to be transmitted into the T helper or T cytotoxic cells. 4…”