The role of Ly49 family of receptors on CD8 T cells

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT We have shown that Ly49 family of surface receptors mark CD8 Tregs in mice. Ly49 refers to a family of receptors for MHC class I that is primarily expressed by natural killer (NK) cells. A subset of CD8 T cells express inhibitory Ly49 family members, which contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains. Beyond their utility as markers of CD8 Tregs, however, the functional contribution of these Ly49 receptors to CD8 Tregs has not been investigated. Ly49+ CD8 T cells have long been known to be highly responsive to IL-15, but the role of IL-15 in the function of CD8 Tregs is also not known. It has also been argued that the transcription factor Helios is needed for CD8 Treg function. Yet experiments to date have not clearly distinguished the role of Helios in the development of CD8 Tregs from the ongoing need for Helios while CD8 Tregs perform their regulatory functions. Integrating our results and these outstanding questions, our central hypothesis is that immunization expands the sub-population of CD8 Tregs that can resolve a given immune response, and Ly49 and Helios are required for the development and function of these CD8 Tregs. The relevance of these questions for human health and disease was made clear by our recent study from us of the human counterpart to Ly49+ CD8 Tregs. In our recent study, we show that KIR+ CD8 T cells were elevated in the blood of celiac disease patients and individuals with several other autoimmune diseases. Our study thus argued that KIR+ CD8 T cells function to suppress self-reactive CD4 T cells and are transcriptionally and phenotypically equivalent to mouse Ly49+ CD8 Tregs. Therefore, a better understanding of the determinants of Ly49+ CD8 Treg function may therefore apply to an important population of human regulatory T cells. The efforts undertaken in this project could help to inform future approaches to harness KIR+ CD8 Tregs for the treatment of autoimmune diseases in human patients.