transforming-growth-factor-beta and West-Nile-Fever

Regulatory T cells (Tregs) are well known for their role in dampening the immune responses to self-Ags and, thereby, limiting autoimmunity. However, they also must permit immune responses to occur against foreign infectious agents. Using a mouse model of West Nile virus infection, we examined the role of Tregs in the generation of effector and memory T cell responses in the secondary lymphoid organs, as well as the infected tissues. We found that Treg numbers and activation increased in both the secondary lymphoid organs and CNS postinfection. Using Foxp3(DTR) knock-in mice, we found that Treg-deficient mice had increased Ag-driven production of IFN-γ from both CD4(+) and CD8(+) T cells in the spleen and CNS during the effector phase. In mice lacking Tregs, there were greater numbers of short-lived effector CD8(+) T cells in the spleen during the peak of the immune response, but the memory CD8(+) T cell response was impaired. Specifically, we demonstrate that Treg-dependent production of TGF-β results in increased expression of CD103 on CD8(+) T cells, thereby allowing for a large pool of resident memory T cells to be maintained in the brain postinfection.

Topics: Animals; Antigens, CD; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Central Nervous System; Forkhead Transcription Factors; Immunologic Memory; Integrin alpha Chains; Interferon-gamma; Mice; Mice, Inbred C57BL; Spleen; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; West Nile Fever; West Nile virus

The Vγ4(+) cells, a subpopulation of peripheral γδ T cells, are involved in West Nile virus (WNV) pathogenesis, but the underlying mechanism remains unclear. In this study, we found that WNV-infected Vγ4(+) cell-depleted mice had lower viremia and a reduced inflammatory response in the brain. The Vγ4(+) cells produced 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. In addition, Vγ4(+) cells of WNV-infected mice had a higher potential for producing TGF-β. The 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.

Topics: Animals; Brain; Female; Interleukin-10; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, gamma-delta; Spleen; T-Lymphocyte Subsets; Transforming Growth Factor beta; Viremia; West Nile Fever; West Nile virus