Endogenous Secondary TCRs Promote Homeostatic Advantage Via Recognition of Self-Antigens

Abstract

Abstract Our laboratory studies how non-thymically selected secondary TCRs contribute to the T cell repertoire. We have previously demonstrated that peripheral T cells naturally expressing 2 TCRs have increased response to autoantigens. We hypothesized that this could promote homeostatic proliferation of T cells expressing 2 TCRs, which may cause autoimmune risk. To examine secondary TCRs in homeostasis, we performed competitive transfers of CFSE-labeled T cells from B6.Ly5.1 and B6.TCRα+/−.Thy1.1 (lacking secondary TCRs) into irradiated B6 recipients. T cells injected at a 1:1 ratio demonstrated a disadvantage for TCRα+/− T cells in lymphopenia-induced proliferation (LIP), with TCRα+/−/wt donor cell ratios of 0.6±0.1 at 8 d after transfer and 0.5±0.4 at 28 d after transfer. T cell population skewing resulted from increased proliferation of wild-type cells. The homeostatic advantage of secondary TCRs was less in chronic LIP (cLIP) (transfer into TCRα-knockout mice), with TCRα+/−/wt donor cell ratios of 0.8±0.3 at 8 d after transfer and 0.7±0.3 at 28 d after transfer. There was no difference between wt and TCRα+/− T cells in proliferative response to stimulation via anti-CD3/CD28, nor were differences observed for expression of CD3, CD5, or CD127. LIP and cLIP depend on signaling through the TCR, though reactivity to self-antigens is thought to drive LIP as opposed to endogenous antigens from commensal microflora in cLIP. Our results suggest that the advantage for secondary TCRs in homeostatic expansion reflects increased ability to interact with self-pMHC antigens. Current effort is focused to understand how this affects protective and autoreactive peripheral T cell repertoires during aging or iatrogenic lymphopenia.