Vγ4+T cells regulate host immune response to West Nile virus infection

Abstract

Vγ4+ cells, a subpopulation of peripheral γδ T cells, are involved in West Nile virus (WNV) pathogenesis, but the underlying mechanism is unclear. In this study, we found that WNV-infected Vγ4+ cell-depleted mice had lower viremia and a reduced inflammatory response in the brain. Vγ4+ cells produced interleukin (IL)-17 during WNV infection, but blocking IL-17 signaling did not affect host susceptibility to WNV encephalitis. We also noted that there was an enhanced magnitude of protective splenic Vγ1+ cell expansion in Vγ4+ cell-depleted mice compared to that in controls during WNV infection. Additionally, Vγ4+ cells of WNV-infected mice had a higher potential for producing transforming growth factor (TGF)-β. γδ T cells of WNV-infected Vγ4+ cell-depleted mice had a higher proliferation rate than those of WNV-infected controls upon ex vivo stimulation with anti-CD3, and this difference was diminished in the presence of TGF-β inhibitor. Finally, Vγ4+ cells of infected mice contributed directly and indirectly to the higher level of IL-10, which is known to play a negative role in immunity against WNV infection. In summary, Vγ4+ cells suppress Vγ1+ cell expansion via TGF-β and increase IL-10 level during WNV infection, which together may lead to higher viremia and enhanced brain inflammation.

Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

“…However, no difference in the WNV burden was observed between anti-IL-17A antibody-treated and control mice (88). In contrast, our results clearly demonstrate that Il17a Ϫ/Ϫ mice are more susceptible to WNV infection.…”

“…It has been reported that mice treated with anti-IL-17A antibody show an approximately 20% reduced survival rate compared to the control mice after a lethal WNV challenge (88). However, no difference in the WNV burden was observed between anti-IL-17A antibody-treated and control mice (88).…”

“…A wide variety of immune cells, including CD4 ϩ Th17 cells, ␥␦-T cells, NK T cells, and CD8 ϩ T cells, can produce IL-17A (23,88). In addition, the IL-17A receptor (IL-17R) is expressed ubiquitously in virtually all cell types and tissues examined (67,68,86).…”

γδ T Cells Play a Protective Role in Chikungunya Virus-Induced Disease

“…Although some host immune pathways have been implicated in the recognition of CHIKV and subsequent induction of protective and pathogenic responses (59,62,67,69,82,(92)(93)(94), the precise mediators and mechanisms of CHIKV pathogenesis are still relatively poorly understood. Given the prevalence of ␥␦ T cells in the skin, the primary site of CHIKV infection, and evidence that this T cell subset plays a role in the pathogenesis of other arboviruses (95)(96)(97)(98), we tested whether ␥␦ T cells played any role in the pathogenesis of CHIKV-induced disease. These studies demonstrated that CHIKV infection leads to significant increases in the prevalence of ␥␦ T cells in both the foot and draining popliteal lymph node and that the absence of these cells leads to enhanced clinical signs of disease as well as CHIKV-induced histopathologic changes.…”

“…In addition to cytokine production, ␥␦ T cells have been described as a bridge between the innate and acquired immune responses by providing for the early and rapid movement and functions of key effector cells, such as neutrophils, macrophages, and NK cells, to the site of infection (74-76, 106, 107) and then downregulating the immune response after the danger has passed, to minimize potential immune-mediated injury (31,72,73,96,97). Monocytes have been shown to play a pathogenic role during CHIKV infection (66), and therefore the finding that monocyte numbers were increased in the foot/ankle of ␥␦ T Ϫ/Ϫ mice suggests that ␥␦ T cells may limit monocytic influx at day 5 and thereby decreasing the damage these cells cause within muscle tissue of the foot (Fig.…”