| The pool of T cells contains populations that are specialized for trafficking into specific peripheral tissues, including the skin and gut. Entry into these tissues is essential to immunity. In this dissertation, we investigated several aspects of T cell trafficking.;Inflamed skin contains CD4 T cell subsets that express different chemokine receptors. We directly compared CD4 T cells from WT, CCR44-/-, CCR6-/- and CCR10-/- mice in assays of skin trafficking. We also assessed the involvement of each receptor in trafficking between dermis and epidermis. CCR4-deficiency reduced accumulation of memory CD4 T cells in skin by approximately 95%, but neither CCR6- nor CCR10-deficiency yielded any detectable effects. No differences in dermal vs. epidermal localization were observed for cells lacking any of these three receptors. Our findings suggest that CCR6 and CCR10 play unknown, non-trafficking roles in cutaneous immunology.;The mechanisms by which gut and skin tropisms of CD4 T cells are determined remain unclear. We comprehensively assessed the generation of trafficking molecules on CD4 T cells after immunization, and assessed the roles that site of proliferation and peripheral tissue inflammation play in determining CD4 T cell tissue tropisms. We found that E-selectin ligand, a skin tropic homing molecule, is only generated by CD4 T cells when accompanied by active skin inflammation, and that CCR9 is most efficiently generated when accompanied by active gut inflammation. Expression of P-selectin ligand and alpha4beta7 integrin were less dependent on barrier tissue inflammation. We also show that skin tropism imprinting is not dependent on Langerin+ DCs. Our findings suggest that evolutionarily barriers to infection are important in determining tissue tropism.;T cell entry into the small intestine requires interaction between CCR9 and CCL25. We tested the ability of a CCR9 antagonist, CCX8037, to inhibit T cell mediated intestinal inflammation. CCX8037 did not affect the gut tropism imprinting on CD8 T cells within the GALT, but did prevent their localization within the small intestine. We also confirmed CCX8037 had no effect on accumulation of T cells within skin. This study demonstrates the feasibility of creating pharmaceuticals capable of modulating local immunity despite systemic administration. |
