CD4+CD25+Foxp3+ regulatory T cells maintain peripheral tolerance in the context of T cell LIP through preservation of TCR diversity

Abstract

T cell diversity is a key feature of the adaptive immune system. Lymphopenia‐induced proliferation (LIP) can trigger oligoclonal expansion of T cells reacting to foreign or self‐antigens. This can result in loss of T cell diversity and compromise immune fitness that can be achieved following reconstitution by LIP. We demonstrate that CD4+CD25+Fopx3+ regulatory T cells selectively inhibit the spontaneous (fast) form of LIP, which is associated with differentiation into memory/effector‐like cells, and is likely to contain the most reactive T cell clones. Selective suppression of these clones is likely to leave more resources for T cells undergoing the slower homeostatic form of LIP. Putting it all together, we hypothesize that one of the functions of Tregs is to maintain the T cell diversity and overall immune fitness during reconstitution from lymphopenia. We are currently testing this hypothesis directly through flow cytometric analysis of TCR V beta usage, PCR‐based TCR J beta spectratyping, and sampling antigen‐specific cells by means of magnetic bead pull‐down with MHC class I and II tetramers.