CD4+ T cell response to food

Project Summary/Abstract It is paradoxical that vertebrates do not develop immunity to their food because many of the proteins in it are completely foreign to their immune systems. This conundrum is particularly relevant for CD4+ T cells, which use T cell antigen receptors (TCRs) to recognize peptides bound to major histocompatibility complex class II (MHCII) molecules and can cause gliadin-induced celiac disease in some people. A failure to reach consensus about how the CD4+ T cell system tolerates food in most individuals but not those with celiac disease is limiting current approaches to treatment. We recently addressed this problem by using peptide:MHCII tetramer-based cell enrichment and flow cytometry to show that CD4+ T cells respond to MHCII-bound food peptides by proliferating weakly in the gut associated lymphoid tissues (GALT). The population that manages to proliferate contains regulatory T (Treg) cells and a hyporesponsive (anergic) conventional T cell population consisting of cells that lack markers of canonical CD4+ T cell subsets (Thlin–) but resemble central memory T (Tcm) cells or follicular helper T (Tfh) cells. In this proposal, we seek to understand how exposure to MHCII-bound food peptides causes cognate T cells to form the Treg and Thlin– subsets and how this process is subverted in celiac disease. We will use gene knockout approaches to identify how the Tfh-like cells form and cell transfer approaches to resolve the precursor-product relationships between the Tfh-like, Tcm-like, and Treg cells. We will use DQ8-Dd-villin-IL-15tg mice that overexpress IL-15 in the gut and develop CD4+ T cell-dependent celiac disease after gliadin ingestion to determine how gliadin peptide:HLA-DQ8-specific T cells become pathogenic. We will use peptide immunotherapy and a Treg cell-promoting IL-2 mutein to see if celiac disease can be prevented and treated. Completion of this research will fill basic knowledge gaps about CD4+ T cell tolerance of food antigens and point to possible therapies for failures of this process that lead to celiac disease.