Prostaglandin E2 and IL-23 plus IL-1β Differentially Regulate the Th1/Th17 Immune Response of Human CD161+CD4+ Memory T Cells

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Abstract
Prostaglandin E2 (PGE2), interleukin (IL)-23, and IL-1beta (beta) propagate inflammatory bowel disease (IBD) by enhancing the development and function of IL-17 producing CD4(+) T helper (Th17) cells. CD4(+) T cells that express the C-type lectin-like receptor CD161 have been proposed to be the physiologic pool of circulating Th17 cells implicated in IBD. We sought to understand how PGE2, alone and in combination with IL-23 and IL-1 beta, modulate human peripheral CD161(+)CD4(+) memory T cells. We found that CD161(+) cells comprise a significant proportion of human peripheral CD4(+) memory T cells. PGE2 and IL-23 plus IL-1 beta synergistically induced early IL-17A secretion from CD161(+)CD4(+) memory T cells and the selective enrichment of IL-17A(+)CD161(+)CD4(+) memory T cells in culture. Conversely, IL-23 plus IL-1 beta partially opposed the PGE2-mediated repression of early interferon gamma (IFN-gamma) secretion from CD161(+) cells, as well as the PGE2-mediated depletion of IFN-gamma(+)CD161(+) cells. Our results suggest that PGE2 and IL-23 plus IL-1 beta induce the Th17 immune response preferentially in CD161(+)CD4(+) memory T cells, while divergently regulating their ability to express IFN-gamma. We hypothesize that Th17-mediated chronic inflammation in IBD depends on the net response of CD161(+)CD4(+) memory T cells to both PGE2 and IL-23 plus IL-1 beta. Clin Trans Sci 2011; Volume 4: 268-273

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