Development of Interactive Immunoregulatory Gr‐1+ Subsets Induced by Mycobacterial Products: Role of IL‐23 in Mobilization from Bone Marrow.

Abstract

Similar to the regulation of vasodilation, the balance between immunosuppressive nitric oxide (NO) and its antagonist superoxide (O2−) regulates expansion of activated T cells in mice. Reduction of NO levels by O2− is essential for T cell expansion and development of autoimmunity. Mice primed with heat‐killed Mycobacterium develop granulocytic Ly‐6G+ and monocytic Ly‐6G− Gr‐1+ subsets in the spleen, which, upon stimulation by activated T cells, produce O2− or NO, respectively, which regulate T‐cell expansion. Here, we report on the development of this ‘Greg system’ in bone marrow (BM). Unlike spleen, naïve BM expressed high levels of Gr‐1+ cells and weak immunoregulatory activity. Upon priming, BM cells expressed strong NO and O2− activity in the Gr‐1 enriched fraction, similar to the spleen, but in addition developed NO activity in the Gr‐1 depleted fraction as well, unlike the spleen. As expected, Ly‐6G+ splenocytes developed poorly in primed IL‐23−/− mice and produced no O2− Unexpectedly, splenocytes expressed reduced NO‐mediated suppression by Gr‐1+ cells as well, indicating a general role for IL‐23 in Greg development. Surprisingly, strong immunoregulatory NO and O2− activities both developed in BM of IL‐23−/− mice. While O2− production was restricted to the Gr‐1+ BM cell fraction, suppressive NO production was strongest in the Gr‐1‐depleted fraction. We conclude that IL‐23 functions at different levels during development of Greg subsets, i.e. mobilization of O2− producing counter‐suppressive granulocytic Greg from BM, and optimal development of suppressive Gr‐1+ monocytic cells within the BM prior to mobilization.