Impact of TCR-peptide/MHC class II affinity on the pathogenicity and regulation of prostate-specific CD4+ T cells

Abstract

Abstract In both humans and mice, self-reactive CD4+ T cells are implicated in a range of autoinflammatory processes. To promote disease, such cells must evade clonal deletion in the thymus, as well as intrinsic and extrinsic regulation mechanisms in the periphery, including anergy and regulatory T cell-mediated suppression. However, the impact of T cell receptor (TCR) - peptide/MHC class II (pMHCII) binding properties on the autoimmune potential of self-specific cells and their susceptibility to immune regulation remains incompletely defined. Much previous work on this topic has relied on the study of T cells reactive to foreign model antigens. However, immune responses towards such antigens may not recapitulate those targeting bona fide self-antigens. Through the in vivo analysis of CD4+ T cell clones reactive to a natural I-Ab-restricted self-peptide derived from the prostate-specific protein Tcaf3 (termed “C4” peptide), we aim to define the role of TCR-pMHCII binding affinity on the pathogenicity and regulation of self-reactive CD4+ T cell clones. Our findings thus far in both tumor-free and prostate-tumor-bearing mice reveal notable differences in the developmental trajectories and peripheral functions of clones with varying TCR affinity for C4/I-Ab. Ongoing work will continue to leverage our novel and physiologically relevant TCR-ligand system to better understand the fundamental mechanisms by which immune tolerance is established and enforced. This work was funded by the following sources (to P.A.S.): R01-CA160371, R01-AI110507, U01-AI154560, a Cancer Research Institute Investigator Award, and the University of Chicago Comprehensive Cancer Center. D.R. was supported by an NIH/NCI F30 predoctoral fellowship (F30-CA247264). V.L. was supported by an NIH/NCI F30 predoctoral fellowship (F30-CA217109). D.R. and V.L. were supported by the University of Chicago Medical Scientist Training Program (T32-GM007281).