Rules of chemokine receptor association with T cell polarization in vivo

TLDR

Existing models of chemokine receptor association with Th1/Th2 polarization overlook the diversity of effector and memory T cells in vivo. We systematically examined how 11 chemokine receptors, alone or in combination, associate with CD4 T cell polarization. We found that any chemokine receptor can be expressed by Th1, Th2, Th0, or nonpolarized CD4 T cells, but each receptor or specific receptor combinations delineate distinct polarized and nonpolarized subsets, with CXCR3/CCR4 patterns distinguishing Th1 from Th2, CCR7+ cells predominating among Th1/Th2 effector cells, and combinatorial receptor expression enabling tissue‑ and subset‑dependent targeting of effector T cells.

Abstract

Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3+CCR4–, and Th2 but only rare Th1 cells are CCR4+CXCR3–. Contrary to recent reports, although CCR7– cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7+ and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.