Innate CD8αα⁺cells and osteopontin promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation

Abstract

20Innate CD8 + cells, also referred to as iCD8 cells, are TCR-negative intraepithelial 21 lymphocytes (IEL) possessing cytokine and chemokine profiles and functions related to innate 22 immune cells. iCD8 cells constitute an important source of osteopontin in the intestinal 23 epithelium. Osteopontin is a pleiotropic cytokine with diverse roles in bone and tissue 24 remodeling, but also has relevant functions in the homeostasis of immune cells. In this report, we 25 present evidence for the role of iCD8 cells and osteopontin in the homeostasis of TCR-negative 26 NKp46 + NK1.1 + IEL (ILC1-like). We show that in the absence of iCD8 cells, the number of 27 NKp46 + NK1.1 + IEL is significantly reduced. These ILC1-like cells are involved in intestinal 28 pathogenesis in the anti-CD40 mouse model of intestinal inflammation. Reduced iCD8 cell 29 numbers and/or osteopontin expression results in a milder form of intestinal inflammation in this 30 disease model. Collectively, our results suggest that iCD8 cells and osteopontin promote 31 survival of NKp46 + NK1.1 + IEL, which significantly impacts the development of intestinal 32 inflammation. 33 34 42 homeostasis of the intestinal epithelium [4-9]. Lately, it has been recognized that the IEL 43 compartment also harbors TCR neg lymphoid cells with critical roles in mucosal immune 44 responses [3]. The great majority of TCR neg IEL is composed of cells expressing intracellular 45 CD3, which can be divided in CD8 + or CD8 -IEL [10]. TCR neg CD8 + IEL, also referred 46 to as innate CD8 (iCD8) cells, have been previously characterized by our group both in mice