Human Vδ2 T cells are a major source of interleukin-9

Abstract

Vδ2Vγ9 T cells are the dominant γδ T-cell subset in human peripheral blood. Vδ2 T cells recognize pyrophosphate molecules derived from microbes or tumor cells; hence, they play a role in antimicrobial and antitumor immunity. TGF-β, together with IL-15, induces a regulatory phenotype in Vδ2 T cells, characterized by forkhead box protein P3 (FoxP3) expression and suppressive activity on CD4 T-cell activation. We performed a genome-wide transcriptome analysis and found that the same conditions (TGF-β plus IL-15) strongly enhanced the expression of additional genes in Vδ2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit alpha E (ITGAE; CD103/αEβ7), and IL9. This up-regulation was associated with potent IL-9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants. In contrast to CD4 and CD8 αβ T cells, γδ T cells did not require IL-4 for induction of intracellular IL-9 expression. Upon antigen restimulation of Vδ2 T cells expanded in vitro in the presence of TGF-β and IL-15, IL-9 was the most abundant among 16 analyzed cytokines and chemokines. IL-9 is a pleiotropic cytokine involved in various (patho)physiological conditions, including allergy and tumor defense, where it can promote antitumor immunity. Given the conspicuous sensitivity of many different tumors to Vδ2 T-cell–mediated killing, the conditions defined here for strong induction of IL-9 might be relevant for the development of Vδ2 T-cell–based immunotherapy.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…[10][11][12][13] Whereas murine cd T cells acquire TCR-dependent functional maturity during thymic ontogeny, human cd thymocytes are functionally immature and instead acquire their effector functions in response to peripheral cytokine signals. [21][22][23][24] While IFN-c-producing cd T cells are abundant in peripheral blood, IL-17 production by human cd T cells is rare at homeostasis. 15 Unlike in mice, the cd T-cell compartment in humans cannot be functionally defined based on differential ULBPs.…”

γδ cells and tumor microenvironment: A helpful or a dangerous liason?

“…The existence of γδ T cells with regulatory functions was demonstrated by Casetti et al., who have reported the induction of Foxp3 + regulatory γδ T cells (γδreg) by TGF‐β1 and IL‐15, accompanied by antigen stimulation, which inhibits the proliferation of anti‐CD3 and anti‐CD28 antibody‐stimulated PBMCs . Surprisingly and in contrast with previous data, Kabelitz and colleagues have observed by genomewide transcriptome analysis that the same cultural conditions (TGF‐β plus IL‐15) strongly enhanced the expression of additional genes in Vδ2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit αE (ITGAE; CD103/αEβ7) and IL‐9 and this up‐regulation was associated with potent IL‐9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants …”

Th9 cells in allergic diseases: A role for the microbiota?

“…IL‐9 is not only made by CD4 T cells, but can be produced by a broad range of immune cells, such as mucosal mast cells, type 2 innate lymphoid cells (ILC2), γδ T cells and CD8 T cells . The downstream functionality of IL‐9 seems to depend on the cellular source as well as the microenvironment of the secreting cells.…”