Transgenic human IL-10 expression by CD4+ T cells is associated with resistance to colitis in Il10-/- mice (59.11)

Abstract

Abstract Studies in mice suggest that the cellular source of the immunoregulatory cytokine IL-10 plays a key role in determining susceptibility to various infectious and autoimmune diseases. To better understand cell-specific human IL-10 (hIL-10) expression we generated a hIL-10 transgenic mouse using a bacterial artificial chromosome (hIL10BAC). Human IL-10 is biologically active in the mouse, and by reconstituting Il10-/- mice with the hIL10BAC we can evaluate the effects of human IL-10 regulation in vivo. We found that the hIL10BAC rescues Il10-/- mice from helicobacter-induced colitis as evidenced by histopathology scores of inflammation and a failure to develop rectal prolaspe. Aberrant proinflammatory cytokine mRNA expression in the colons of Il10-/- mice was reduced in Il10-/-/hIL10BAC mice. Likewise, the percentages of IL-17-expressing CD4+ T cells in the ileal and colonic lamina propria were normalized to WT levels in Il10-/-/hIL10BAC mice. In searching for cellular sources of hIL-10 we found that hIL-10 expression was enriched specifically within the colonic lamina propria and these cells were CD4+CD25+Foxp3+ T cells. Adoptive transfer of CD4+ Il10-/-/hIL10BAC T cells protected Rag1-/- mice from wasting disease using a T cell transfer model of colitis. These data combined with previous results from our laboratory suggests that human IL-10 expression in various CD4+ T cell subsets is under different regulatory constraints.