Until recently, inflammatory chemokines were still considered to be the "goalkeepers" necessary for immunity and inflammation. The chemokines associated with γδ T cells also have the power that cannot be ignored.
Introduction to Chemokines
γδ T cells are a unique subgroup of T lymphocytes. At the level of effector cells, they have strong cytotoxic activity and the ability to produce a variety of cytokines, just like the traditional αβ T lymphocytes. These include protein chemokines, which play an important role in leukocyte migration, activation, and threshing. In terms of T lymphocyte biology, chemokines and their corresponding cellular receptors are involved in the development of T cells in the thymus, the arrangement of T-B cell interactions, the differentiation of effector T cells, and the development of memory T cells. The regulation of chemokine receptors and the production pattern of local chemokines play an important role in the localization of γδ T cells under physiological and pathophysiological conditions such as infection, inflammation, and tumor defense.
Regulation of Chemokines Production by γδ T Cells
The functional study of purified and cloned γδ T cells showed that human γδ T cells migrated under the action of CC chemokines such as C-C chemokine ligand 5 (CCL5), monocyte chemoattractant protein 1 (MCP-1 or CCL2), macrophage inflammatory protein 1α (MIP-1α or CCL3) and MIP-1β (CCL4), but did not reverse CXC chemokine IL-8 (CXCL8) or interferon (IFN)-induced protein 10 (IP-10 or CXCL10). Recently, RNase protection experiments have shown that the expression of CC chemokine receptors, especially CCR5, in Vδ2 γδ T cell lines activated by phosphorylated antigens was rapidly down-regulated after re-exposure to isopentenyl pyrophosphate (IPP). Besides, CXCR3 expression was found in TCR γδ-expressing thymocytes. These thymocytes responded to the corresponding ligand IP-10 (CXCL10), IFN-γ (or CXCL9) induced single factor and IFN induced T cell α-chemoattractant (or CXCL11).
Fig.1 Mechanism of γδ T cell function. (Paul, 2014)
Relationship Between IL-22 Expressing γδ T Cells and Diseases
Chemokines and chemokine receptors play an important role in the migration of T lymphocytes, not only for αβ T cells but also for γδ T cells. At present, the important role of several chemokines in different diseases is being studied.
Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although γδ T lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by limited knowledge of the molecular cues that determine γδ T cell migration toward tumors in vivo. The research has set out to identify the chemotactic signals that orchestrate tumor infiltration by γδ T cells, which has used the preclinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on γδ TIL recruitment in vivo. It has been proved that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-g and display potent cytotoxic functions. Moreover, CCL2 directed γδ T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing Abs. Strikingly, the lack of γδ TILs in TCRd-deficient but also in CCR2- deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells. Importantly, it has demonstrated that human Vδ1 T cells, but not their Vδ2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver, or breast cancer. Research has identified a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vδ1 T cells in cancer immunotherapy.
CCL2 is a small, secreted, chemokine. Studies have shown that human Vδ1 T cells (rather than Vδ2 corresponding cells) express CCR2 and migrate to CCL2. The expression of CCL2 is strongly deregulated in various human tumors, such as lung cancer, prostate cancer, liver cancer or breast cancer. This also confirmed a new protective effect of CCL2 in tumor microenvironment.
In addition to pro-inflammatory activity, CCL3 also negatively regulates the proliferation of hematopoietic stem/progenitor cells (HSPC). CCL3 can alternatively be called a stem cell inhibitor. This characteristic has prompted many researchers to study the effect of CCL3 on the pathophysiological process of normal physiological hematopoietic and hematopoietic malignant tumors.
CCL4 has chemotaxis on different types of cells, including macrophages, natural killer cells, monocytes, immature dendritic cells and coronary artery endothelial cells. Studies have shown that the mechanisms related to CCL4 (CCL4 and its receptors) may provide potential therapeutic targets for DM and/or atherosclerotic cardiovascular disease.
CCL5 can induce the migration and recruitment of T cells, dendritic cells, eosinophils, NK cells, mast cells and basophils. The role of CCL5 has been demonstrated in several studies of human diseases. This includes targeting chronic lung diseases, driving angiogenesis and tumor growth, and playing a related role in the immune response to certain infections (especially viral infections).
Important issues for future research on chemokine/chemokine receptor systems and γδ T cells include accurate characterization of the chemokine receptor patterns of γδ T cell subsets in health and disease, as well as the characteristics of regulatory interactions between γδ T cells and adjacent αβ T cells or epithelial cells.
- Paul, S., et al. Phenotypic and Functional Plasticity of Gamma-Delta (γδ) T Cells in Inflammation and Tolerance. International reviews of immunology. 2014, 33(6): 537-558.