Regulated release of nitric oxide by fibroblastic reticular cells controls the frequency and pathogenicity of autoreactive T cells in a model of intestinal tolerance (44.37)

Abstract

Abstract Fibroblastic reticular cells (FRCs) are non-hematopoietic stromal cells of lymphoid organs wielding significant immunological impact. They exert important effects on the migration and homeostasis of naïve T cells however, their influence on activated T cells is undescribed. Here we report that nitric oxide (NO) release by FRCs profoundly inhibits T cell proliferation without altering early activation signals. Mechanistically, the expression of nitric oxide synthase 2 and production of NO paralleled the activation of T cells and required a tripartite synergism between IFNgamma, TNFalpha, and direct contact with activated CD8 T cells. We have also assesed the role of NOS2 in the iFABP-tOVA transgenic mouse model in which a truncated, cytosolic form of ovalbumin (tOVA136-336) is expressed as a self-antigen by mature intestinal epithelial cells under the control of the intestinal fatty acid binding protein (iFABP) promoter. In this model, where FRCs play a major role in the induction of CD8 T cell tolerance, FRC-derived NO controlled the magnitude of the response at the level of T cell proliferation. The percentage and absolute number of self-reactive CD8 T cells was increased in NOS2-/- iFABP mice, resulting in increased weight loss and more severe ileocolitis. Our study illuminates a hitherto unrecognized role of FRCs in regulating T cell responses that may have important implications for inflammatory bowel diseases.