Interleukin 15 and CD4+ T Cells Cooperate to Promote Small Intestinal Enteropathy in Response to Dietary Antigen

Abstract

CD4(+) T cells specific for dietary gluten and interleukin 15 (IL15) contribute to the pathogenesis of celiac disease. We investigated whether and how they interact to damage the intestine using mice that overexpress human IL15 in the intestinal epithelium and have CD4(+) T cells specific for ovalbumin, a dietary antigen. We crossed mice with CD4(+) T cells specific for ovalbumin (OTII) with mice that overexpress human IL15 under an intestine-specific promoter (B6× IL15Tge). The offspring (OTII× IL15Tge mice) received control or ovalbumin-containing diets until 3 months of age. Enteropathy was monitored by weight, ratio of villous:crypt length, and the number of intestinal lymphocytes. Phenotype, cytokine production, and degranulation of mucosal and spleen lymphocytes were analyzed by multicolor flow cytometry or enzyme-linked immunosorbent assay. Regulatory T-cell function and CD8(+) T-cell activation were analyzed in co-culture assays. Exposure to ovalbumin reduced growth and led to enteropathy in OTII× IL15Tge mice but not in control OTII× B6 littermates. Enteropathy was associated with expansion of mucosal granzyme B(+) CD8(+) T cells, and developed despite increased frequency of functional ovalbumin-specific regulatory T cells. Ovalbumin-activated CD4(+) T cells secreted IL2, which along with IL15 stimulated expansion of noncognate intestinal cytotoxic CD8(+) T cells, which did not respond to regulatory T cells and induced epithelial damage. We observed that in mice given food antigen, cooperation between IL15 and CD4(+) T cells is necessary and sufficient to activate CD8(+) T cells and damage the small intestine. We propose that this process is involved in the development of celiac disease.