CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile

The chemokine receptor CCR9 is expressed on most small intestinal lamina propria and intraepithelial lymphocytes and on a small subset of peripheral blood lymphocytes. CCR9-expressing lymphocytes may play an important role in small bowel immunity and inflammation. We studied the phenotype and functional characteristics of CCR9⁺ lymphocytes in blood from normal donors. A subset of CCR9⁺ T cells have a phenotype of activated cells and constitutively express the costimulatory molecules CD40L and OX-40. In contrast to CCR9^-, CCR9⁺CD4⁺ peripheral blood T cells proliferate to anti-CD3 or anti-CD2 stimulation and produce high levels of IFN-γ and IL-10. IL-10-producing cells were exclusively detected within the CCR9⁺ subset of CD4⁺ T cells by intracellular staining and were distinct from IL-2- and IFN-γ-producing cells. Moreover, memory CCR9⁺CD4⁺ lymphocytes respond to CD2 stimulation with proliferation and IFN-γ/IL-10 production, whereas memory CCR9^-CD4⁺ cells were unresponsive. In addition, memory CCR9⁺CD4⁺ T cells support Ig production by cocultured CD19⁺ B cells in the absence of prior T cell activation or addition of exogenous cytokines. Our data show that the memory subset of circulating CCR9⁺CD4⁺ T cells has characteristics of mucosal T lymphocytes and contains cells with either Th1 or T-regulatory 1 cytokine profiles. Studies on the cytokine profile and Ag specificity of this cell subset could provide important insight into small intestinal immune-mediated diseases and oral tolerance in humans.