Colitogenic effector T cells: roles of gut homing integrin, gut antigen specificity, and γδ T cells

Disturbance of T cell homeostasis could lead to intestinal inflammation. Naïve CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1 and/or Th17 type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mLN resident CD11b+ dendritic cell subsets via TGFβ/retinoic acid-dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut homing specificity, expression of gut Ag specificity was also crucial. T cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T cell mediated colitis. Importantly, IL-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways