Cytokines

Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction. Cytokines include interferon-gamma (IFN-γ), tumor necrosis factor-α (TNF-α), tumor necrosis factor-α (TGF-β), interleukin 17 (IL-17), interleukin 10 (IL-10), interleukin 4 (IL-4), interleukin 9 (IL-9), and interleukin 22 (IL-22) and so on.

IFN-γ and γδ T Cells

Interferon-γ (IFN-γ) is produced mainly by lymphocytes, such as αβ T cells, natural killer (NK) cells, and γδ T cells. γδ T cells and NK cells are considered to be important IFN-γ producers in blood-stage malaria infections and to be associated with the control of malarial parasites. In the early stages of malaria infection, γδ T cells directly recognize the pathogen through major histocompatibility complex (MHC)-independent mechanisms that involve the γδ TCR, and high levels of IFN-γ production and proliferation are induced.

Table.1 Comparison of human type I, type II, and Type III IFN production and signaling. (Castro, 2018)

TNF-α and γδ T Cells

TNFα is a cell-signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. Human Vγ2Vδ2 T cell responses to phosphoantigen, including activation, proliferation, cytokine production, and tumor cell cytotoxicity, require TNF-α binding to its receptor.

TGF-β and γδ T Cells

TGF-β is regarded as a major immunosuppressive factor in the tumor microenvironment where it is produced in large amounts by tumor cells as well as by cancer-associated fibroblasts, macrophages, and regulatory T cells (Treg). TGF-β is also a key factor for the induction of immunosuppressive γδ T cells. TGF-β is required for human Vδ2 T cells to acquire a regulatory or IL-17-producing phenotype.

Fig.1 Role of TGF-β in the regulation of the cell cycle. (Bešše, 2012)

IL-17 and γδ T Cells

γδ T cells produce IL-17 (γδT17 or γδ17, Tγδ17) which has the function of antimicrobial immunity in the lung, skin, liver, peritoneal cavity. However, aberrant γδT17 cell activity promotes autoimmune inflammation in numerous murine models.

Fig.2 Beneficial and detrimental functions of local and infiltrating γδT17 cells. (Mckenzie, 2018)

IL-10 and γδ T Cells

IL-10 is a cytokine with multiple pleiotropic effects in immunoregulation, and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. γδ T cells play an important role in preventing immune elimination of this tumor by a mechanism that directly or indirectly involves IL-10.

IL-4 and γδ T Cells

Interleukin 4 has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation of B cells into plasma cells. It is a key regulator in humoral and adaptive immunity. Mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice.

Fig.3 Evolutionary timelines of IL-4, IL-13, and their receptors, neutrophils, and adaptive immunity. (Heeb, 2020)

IL-9 and γδ T Cells

IL-9 is a cytokine involved in various (patho) physiological conditions such as allergy and tumor defense. It can promote antitumor immunity. Vδ2 T cells are the main cell population of γδ T cell subset and are a major source of IL-9 in human peripheral blood. In the presence of TGF-β and IL-15, Vδ2 T cells stimulated by antigens will produce a large amount of IL-9, which plays an important role in Vδ2 T cell-mediated antitumor immunity.

IL-22 and γδ T Cells

IL-22 is produced by several populations of immune cells at a site of inflammation, which has functions in non-hematopoietic epithelial cells and fibroblasts. The presence of protective γδ T cells and IL-22 diminished the recruitment of CD4+ T cells to the lung.

Fig.4 Target tissues and physiological effects of IL-22. (Dudakov, 2015)

Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis. Creative Biolabs explains different cytokines activities such as comprising pro- and anti-inflammatory action, cellular immune responses, and performance in hematopoiesis. If you have any questions, please contact us.

References

1. Castro, Flávia.; et al. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Frontiers in Immunology. 2018, 9: 847.
2. Bešše, Lenka.; et al. TGF-β - an excellent servant but a bad master. Journal of Translational Medicine. 2012, 10(1).
3. Mckenzie, D. R.; et al. The Emerging Complexity of γδT17 Cells. Other. 2018, 9.
4. Heeb, L. E. M.; et al. Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils. Genes and Immunity. 2020 (12): 1-7.
5. Dudakov, J. A.; et al. Interleukin-22: immunobiology and pathology. Annual Review of Immunology. 2015, 33(1): 747-785.