Figure 2.

Induction of tissue-specific MR profile. Expression of distinct MR combinations results in tissue-specific migration. T cells that are primed in gut-associated lymphoid tissues preferentially express functional PSGL-1, α₄β₇, and CCR9, which support migration through the post capillary venules of the small intestine to enter the lamina propria and intraepithelial compartment (panel 1). CD103-expressing DC impart the intestinal homing signature on T cells during priming by expression of retinoic acid (RA) in response to microbiota-driven toll-like receptor (TLR) signaling. A different program of MR usage is induced during priming of naïve T cells in skin-draining LN (panel 2). T cells in the skin express the cutaneous lymphocyte antigen (CLA), an inducible carbohydrate modification of PSGL-1, CCR4, CCR8, CCR10, α₄β₁, and LFA-1, which mitigates their migration into the skin. Analogous to intestinal imprinting, CCR10, but not CCR4, expression is regulated by skin-draining DCs that synthesize the vitamin D3 metabolite, 1,25(OH)₂D₃. 1,25(OH)₂D₃ suppresses α₄β₇ and CCR9 expression and RA inhibits CCR4 and CCR10 expression. In addition, CCR8 expression is imprinted by epidermal keratinocytes, although the skin-specific factors that induce CCR8 remain unknown. Evidence for imprinting of T cells in the lung is limited, but recent evidence suggests that lung DC-activated T cell migrate more efficiently into the lung, which was attributed to CCR4, although other MR are likely to contribute (panel 3). Many lymphocytes in the lung express high levels of α₄β₁, α₁β₁, and LFA-1 and CD8+ T cells primed in the mediastinal LN are enriched for CCR5 and CXCR3 expression, suggesting a pulmonary profile driven by distinct molecular mechanisms.