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. 2001 Nov;108(9):1331-9.
doi: 10.1172/JCI13543.

Rules of chemokine receptor association with T cell polarization in vivo

C H Kim  1 , L Rott, E J Kunkel, M C Genovese, D P Andrew, L Wu, E C Butcher
Affiliations

Rules of chemokine receptor association with T cell polarization in vivo

V体育官网入口 - C H Kim et al. J Clin Invest. 2001 Nov.

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 VSports手机版. 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. .

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Figures

Figure 1
Figure 1
Profiles of polarized and nonpolarized T cell frequencies in CKR+ memory CD4 T cell populations. (a) Expression of CKRs on total (left, FACS plots) and memory CD4 T cells (right, histogram). Frequencies of Th1 (IFN-γ+ IL-4–), Th2 (IL-4+ IFN-γ–), Th0 (IFN-γ+ IL-4+), or Tnp (IFN-γ– IL-4–) cells in total, memory, or CKR-expressing memory CD4 T cell populations are shown as dot plots (b) and graphs (c). Peripheral blood CD4 T cells were activated by PMA and ionomycin for 4 hours before cytokine analysis. Each CKR+/– population is gated (b and c). Averages from 6–11 different donors are shown.
Figure 2
Figure 2
CKR expression by Th1, Th2, Th0, and Tnp cell populations. Percentage of peripheral blood Th1, Th2, Th0, and nonpolarized cells expressing each CKR was examined by gating on Th1 (IFN-γ+ IL-4–), Th2 (IL-4+ IFN-γ–), Th0 (IFN-γ+ IL-4+), or Tnp (IFN-γ– IL-4–) cells. Averages from at least six different donors with SDs.
Figure 3
Figure 3
Polarized T cell populations are enriched in frequency among CCR7– T cells, but are predominantly CCR7+. (a) The frequencies of IL-4– or IFN-γ–producing cells are shown as percentage of each CKR-positive or -negative subset by gating on naive (CD45RA+), CCR7+, CCR7–, CXCR5+, or CXCR5–CD45RO+ CD4 T cell population. (b) The absolute frequency (%) of IL-4– or IFN-γ–producing cells among CCR7+/– or CXCR5+/–CD45RO+ subsets in blood CD4 T cells. The absolute frequency (%) was obtained by normalizing (i.e., multiplying) the frequencies of IL-4– or IFN-γ–producing cells in each subset (the values in the a) by the frequency of each memory subset in total CD4 T cells (0.42 for CCR7+; 0.11 for CCR7–; 0.1 for CXCR5+; 0.43 for CXCR5–; n = 8). CD4 cells (5 × 104) were acquired for each analysis. Results from four donors are shown.
Figure 4
Figure 4
Polarized CD4 T cell populations defined by CXCR3 and CCR4 in combination. (a) Coexpression of CXCR3 and CCR4, and (b) frequencies of Th1, Th2, and Th0 cells in CCR4+CXCR3–, CCR4+CXCR3+, and CCR4–CXCR3+ populations. Each subset was individually sorted from peripheral blood CD4 T cells for cytokine analyses. (c) Expression of CXCR3 and CCR4 and frequencies of Th1 and Th2 cells in the CLA+/– (skin-homing receptor) memory CD4 T cell subsets. Representative of four independent experiments.
Figure 5
Figure 5
CKR association with T cell polarization in inflammatory tissues (CD4 T cells in psoriatic arthritic synovial fluid). (a) CKR expression by synovial CD4 T cells. (b) CD45RA and CD45RO expression by synovial CD4 T cells. (c) Coexpression of CXCR3 and CCR4 by synovial fluid CD4 T cells. (d) Intracellular IFN-γ and IL-4 production pattern of arthritic synovial CD4 T cells. (e) Frequencies of Th1 (IFN-γ+ IL-4–), Th2 (IL-4+ IFN-γ–), Th0 (IFN-γ+ IL-4+), or Tnp (IFN-γ– IL-4–) cells in CKR-expressing CD4 T cell populations are shown. (f) Expression of CKRs by Th1, Th2, Th0, and Tnp cells in arthritis synovial fluid. Prestained cells with anti-CKR and anti-CD4 were activated by PMA and ionomycin for 4 hours in the presence of monensin before intracellular staining of IFN-γ and IL-4. Representative data from three different experiments are shown.
Figure 6
Figure 6
Dependence of Th1-containing populations on coexpression of CXCR3. Peripheral blood CD4 T cells expressing CXCR3 and/or another CKR among CCR5 (a), CCR2 (b), CCR6 (c), or CXCR5 (d) are shown along with frequencies of Th1 and Th2 cells. Each subset was sorted after staining with Ab’s to CKRs, stimulated with PMA and ionomycin, and examined for production of IL-4 and/or IFN-γ. Results from three to four donors are shown.
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