Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen

Abstract

SUMMARY Regulatory T (Treg) cells expressing the transcription factor Foxp3 are critical for the prevention of autoimmunity and the suppression of anti-tumor immunity. The major self antigens recognized by Treg cells remain undefined, representing a substantial barrier to the understanding of immune regulation. Here, we have identified natural Treg cell ligands in mice. We found that two recurrent Treg cell clones, one prevalent in prostate tumors and the second associated with prostatic autoimmune lesions, recognized distinct non-overlapping MHC class-II-restricted peptides derived from the same prostate-specific protein. Notably, this protein is frequently targeted by autoantibodies in experimental models of prostatic autoimmunity. Based on these findings, we propose a model in which Treg cell responses at peripheral sites converge on those self proteins that are most susceptible to autoimmune attack, and we suggest that this link may be exploited as a generalizable strategy to identify the Treg cell antigens relevant to human autoimmunity.

Prolongation of allograft survival by passenger donor regulatory T cells

“…Although the precise target epitopes remain ill-defined, 16,17 nT-regs are thought to recognize specific, self-restricted peptide epitopes (typically autoantigens 18 ). Although the precise target epitopes remain ill-defined, 16,17 nT-regs are thought to recognize specific, self-restricted peptide epitopes (typically autoantigens 18 ).…”

“…It is perhaps surprising that donor-derived nT-regs were more effective than recipient-derived nT-regs at blocking host humoral responses. Although the precise target epitopes remain ill-defined, 16,17 nT-regs are thought to recognize specific, self-restricted peptide epitopes (typically autoantigens 18 ). Donor-derived nT-regs therefore presumably recognize intact host MHC class II complexes on recipient cells via the direct pathway, 19 and in which case, do so with a much greater precursor frequency than for a self-restricted response, with approximately 5% of the clonal repertoire responding.…”

Autoimmune Polyendocrine Syndromes

“…Recent findings indicate that Aire controls immune tolerance by an additional mechanism—the induction of a unique population of FOXP3-positive T regulatory cells (Tregs) in the thymus that have the ability to suppress autoreactive cells. 16,17 Thus, not only do more autoreactive cells escape deletion, but those Tregs normally in place to limit their activities are either not developed or are dysfunctional (Fig. 2A).…”

A review on the interactions between the tumor microenvironment and androgen receptor signaling in prostate cancer

“…The immune response in CaP is predominantly via the adaptive immune system, particularly CD8+ T-cells, with extensive infiltration observed following the transition from normal prostatic tissue to CaP. The adaptive immune response generates a range of CD4+ T cell clones that express unique T-cell receptors that recognize antigen presenting major histocompatibility complex class II (MHC-II) (52). The majority of findings previously published highlight a pro-tumourigenic effect of specific immune cells on CaP.…”