IL-21 inhibits IL-17A-producing γδ T-cell response after infection with Bacillus Calmette-Guérin via induction of apoptosis

Abstract

Innate γδ T cells expressing Vγ6 produce IL-17A at an early stage following infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In this study, we used IL-21 receptor knockout (IL-21R KO) mice and IL-21-producing recombinant BCG mice (rBCG-Ag85B-IL-21) to examine the role of IL-21 in the regulation of IL-17A-producing innate γδ T-cell response following BCG infection. IL-17A-producing Vγ6 γδ T cells increased in the peritoneal cavity of IL-21R KO mice more than in wild type mice after BCG infection. In contrast, the number of IL-17A-producing Vγ6 γδ T cells was significantly lower after inoculation with rBCG-Ag85B-IL-21 compared with control rBCG-Ag85B. Notably, exogenous IL-21 selectively induced apoptosis of IL-17A-producing Vγ6 γδ T cells via Bim. Thus, these results suggest that IL-21 acts as a potent inhibitor of a IL-17A-producing γδ T-cell subset during BCG infection.

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

“…20 TCR γδ T cells can be one of the main sources of IL-17 responding to IL-23 stimulation. 52 Our studies recently showed that IL-23 and other Th17-related cytokines can induce proliferation and expansion of Vγ2Vδ2 T cells in the presence of HMBPP. 23 Mycobacteria vaccination/infection of macaques enhances the ability of IL-23 to expand HMBPP-activated Vγ2Vδ2 T cells, and those expanded cells have multieffector functions for producing cytokines of IL-17, IL-22, IL-2 and IFN-γ.…”

Gamma-delta (γδ) T cells: friend or foe in cancer development?

“…There are also some cytokines in the TME that enhance the antitumor function of γδ T cells and inhibit the protumor γδ T cells responses. As IL-21 has been proven capable of inhibiting γδ T 17 cell protumor cell responses, further research on IL-21 should be conducted in human cancer [ 106 ]. It has been shown that IL-36γ acts synergistically with TCR signaling and/or that IL-12 can stimulate γδ T cells.…”

Interleukin-21 Induces Short-Lived Effector CD8 + T Cells but Does Not Inhibit Their Exhaustion after Mycobacterium bovis BCG Infection in Mice

“…OVA-expressing recombinant BCG (rBCG-OVA) has been described previously (43). To construct rBCG-Ag85B-IL-21 or rBCG-Ag85B, pNN2-mIL-21-Ag85B or pNN2-Ag85B was introduced into BCG (strain Tokyo 172) by electroporation as reported previously (42,44,47).…”

“…Bacterial infection. The culture method for rBCG-OVA, rBCG-Ag85B-IL-21, or rBCG-Ag85B has been described previously (42,48). Mice were inoculated intratracheally (i.t.)…”

“…CD8 ؉ T cell response after rBCG-Ag85B-IL-21 infection. To elucidate the effects of IL-21 on CD8 ϩ T cell responses to BCG infection under conditions of IL-21 overexpression, we used rBCG-IL-21-Ag85B, secreting the IL-21-Ag85B fusion protein, which can be detected by an enzyme-linked immunosorbent assay (ELISA) with an anti-IL-21 monoclonal antibody (MAb) (42). The level of TB10.4-or Mtb32a-specific CD8 ϩ T cells was examined after intratracheal (i.t.)…”