Dysregulation of iCD8α cells promotes susceptibility to intestinal inflammation

Abstract

Abstract iCD8α cells are a population of innate immune cells present in the intestinal intraepithelial lymphocyte (IEL) compartment, characterized by the expression of CD8αα. We have shown that iCD8α cells play a critical role during immune responses in the intestinal mucosa, however, little is known about the role of iCD8α cells during inflammatory processes of the intestines. The thymus leukemia (TL) antigen is predominantly expressed by intestinal epithelial cells and preferentially interacts with CD8aa. We have shown that CD8αα+ IEL from TL-deficient mice have increased cytokine production and proliferation, indicating that TL controls CD8αα+ IEL effector functions. Rag-deficient mice facilitate the study of innate immune cells, and are an excellent model for the study of iCD8α cells because these cells are the only CD8αα+ IEL present in these mice. Here we present evidence showing that TL regulates the functions of iCD8α cells. Using the anti-CD40 antibody model of colitis, we show that TL−/−Rag-2−/− mice lose more weight, have higher mortality, have more colon damage, and present higher levels of pro-inflammatory cytokines (IFN-γ, IL-6 and OPN) than colons from Rag-2−/− mice. Interestingly, we show that colons and iCD8α cells from TL-deficient mice produce more granzyme than colons or iCD8α cells from TL-competent mice. Moreover, stimulation of iCD8α cells with the pro-inflammatory cytokine IL-12 in vitro induces granzyme secretion. Therefore, we propose that the increased colon inflammation observed in TL-deficient mice is due to: a) dysregulation of iCD8α cells by the lack of TL, and b) increased granzyme secretion by iCD8α cells which may serve as a pro-inflammatory signal.