Both Innate Immune and Epithelial HSP70 Are Essential for Regulation of Intestinal Homeostasis and Development of Experimental Colitis

Abstract

[Background and Aim] Natural killer (NK) cells are associated with regulation of acquired immune responses related to inflammatory diseases such as experimental autoimmune encephalomyelitis and colitis. However, the detail mechanism of NK cell-regulation of pathogenic T cell in inflammation remains unclear. We therefore examine the role of NK cells in a murine model of chronic colitis. [Methods and Results] Anti-asialo GM1 (ASGM1) Ab was injected into RAG deficient (RAG-/-) mice in order to deplete NK cells, followed by adoptive transfer of CD62L+ CD44(naive) T cells. The NK cell depletion interestingly resulted in an increase of CD62LCD44T cells in the spleen and the mesenteric lymph nodes 5 days after T cell reconstitution despite slight exacerbation of colitis compared to mice without NK cell depletion. Flow cytometric analysis showed the CD62Land CD44T cell subset to be Qa-1DR5Lo IL-7R+, while the CD62LCD44+ effecter/memory T cells (TEM) expressed Qa-1+ DR5Hi IL-7R+, suggesting that CD62LCD44T cells are regulated by NK cells in a different mechanism from that of TEM by NK cells via apoptosis. Neither the cytotoxic activity nor the surface markers of NK cells, such as NKG2A/C/E, NKG2D, Ly49, CD94, KLRG1, CD11b and CD27, were affected in the presence or absence of IL-7. Our interest in IL-7 stems from our previous report that IL-7 deficiency completely abrogates colitis in RAG-/mice receiving naive T cells. It had been suggested that such abrogation of colitis may be associated with not only the lack of IL-7 but also another mechanism by which the development of colitis is suppressed at the early stage. Therefore, anti-ASGM1 Ab was injected into RAG-/IL-7-/(DKO) mice receiving naive T cells. The NK cell depletion at the early stage during the induction of colitis resulted in severe colitis in the DKO mice with associated increase in the production of proinflammatory cytokines such as IFN-γ. [Conclusions]Our study suggests that the development of TEM, which induces chronic inflammation, through CD62LCD44T cell subset may be affected by both the presence of NK cells and IL-7, and regulating these mechanisms could be a potential therapeutic target for IBD.