Patterns of Chemokine Receptor Expression on Peripheral Blood γδ T Lymphocytes: Strong Expression of CCR5 Is a Selective Feature of Vδ2/Vγ9 γδ T Cells

Abstract

γδ T lymphocytes play an important role in the immune defense against infection, based on the unique reactivity of human Vδ2Vγ9 γδ T cells toward bacterial phosphoantigens. Chemokines and their corresponding receptors orchestrate numerous cellular reactions, including leukocyte migration, activation, and degranulation. In this study we investigated the expression of various receptors for inflammatory and homeostatic chemokines on peripheral blood γδ T cells and compared their expression patterns with those on αβ T cells. Although several of the analyzed receptors (including CCR6, CCR7, CXCR4, and CXCR5) were not differentially expressed on γδ vs αβ T cells, γδ T cells expressed strongly increased levels of the RANTES/macrophage inflammatory protein-1α/-1β receptor CCR5 and also enhanced levels of CCR1–3 and CXCR1–3. CCR5 expression was restricted to Vδ2 γδ T cells, while the minor subset of Vδ1 γδ T cells preferentially expressed CXCR1. Stimulation with heat-killed extracts of Mycobacterium tuberculosis down-modulated cell surface expression of CCR5 on γδ T cells in a macrophage-dependent manner, while synthetic phosphoantigen isopentenyl pyrophosphate and CCR5 ligands directly triggered CCR5 down-modulation on γδ T cells. The functionality of chemokine receptors CCR5 and CXCR3 on γδ T cells was demonstrated by Ca2+ mobilization and chemotactic response to the respective chemokines. Our results identify high level expression of CCR5 as a characteristic and selective feature of circulating Vδ2 γδ T cells, which is in line with their suspected function as Th1 effector T cells.

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…Interestingly, it has been shown recently that granzyme A produced by adult Vγ9Vδ2 T cells, independently of perforin and granzyme B, induces macrophages to inhibit the growth of intracellular mycobacteria (77). Fetal Vγ9Vδ2 T-cell effectors expressed high levels of the inflammatory chemokine receptors CCR5 and CXCR3, which have been described as being particularly highly expressed on adult blood Vγ9Vδ2 T cells (78). Thus, it seems that this feature of adult Vγ9Vδ2 T cells, like other features, such as their high capacity to produce IFN-γ and granzymes A/K, already is programmed within the fetus rather than being a consequence of exposure to phosphoantigens after birth and associated differentiation.…”

CD3 expression distinguishes two γδT cell receptor subsets with different phenotype and effector function in tuberculous pleurisy

“…In particular, pleural mesothelial cells are responsible in part for initiating the inflammatory response by recruiting mononuclear cells from the vascular compartment into the pleural space through chemokine receptors and their ligands [44]. A weak CCR7 expression in ex-vivo gdT cells from healthy individuals has been found, the majority being CD45RO + cells [45], and stimulation with heat-killed extracts of Mtb downmodulates CCR5 expression on gdT cells [45]. gdTCR triggering induces early and transient CCR7 up-regulation, regarded as a marker of early activation in these cells, together with high CXCR3 expression [46].…”

Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes

“…23,24 CCR5, a receptor for CCL3, CCL4 and CCL5 is strongly expressed on gd T cells compared with ab T cells. 25 Recently, it has been reported that CCL2, CCL3 and CCL5 play an essential role not only in inflammatory diseases but also in several cancers, suggesting that gd T cells could access to the tumor local sites directly without detouring around the lymph nodes. [23][24][25][26][27] In addition, Gong et al 28 reported that in vitro activation of Vg9Vd2 T cells by phosphoantigen and IL-2 down-regulated the IL-2-induced expansion of CD4 + CD25 + FoxP3 + regulatory T cells.…”

“…25 Recently, it has been reported that CCL2, CCL3 and CCL5 play an essential role not only in inflammatory diseases but also in several cancers, suggesting that gd T cells could access to the tumor local sites directly without detouring around the lymph nodes. [23][24][25][26][27] In addition, Gong et al 28 reported that in vitro activation of Vg9Vd2 T cells by phosphoantigen and IL-2 down-regulated the IL-2-induced expansion of CD4 + CD25 + FoxP3 + regulatory T cells. It is also speculated that early IFN-g secretion through either ab or gd TCR enhances immunogenicity of tumors through mechanisms such as increased MHC expression on tumor cells, inhibit the induction of CD4 + CD25 + regulatory T cells and further promotes ab TCR recognition of target cells, 8,29,30 thus providing a positive feedback loop for anti-tumor immune responses.…”