This application will evaluate the role of T cell secreting the pro-inflammatory cytokine IL-17 in virus infections. The IL-17-producing T cells may function to protect from infection or may mediate inflammation and immunopathology. IFN is known to promote the development of Th1/Tc1 cells while it inhibits the formation of IL-17 producing T cells. ? ? The vaccinia virus model will be investigated. The hypothesis is that vaccinia virus may promote the generation of IL-17-producing T cells because: (1) vaccinia virus drives the production of cytokines important for the differentiation of IL-17-producing T cells (IL-6, TGFbeta1, TNFalpha); and (2) vaccinia virus encodes immunomodulatory proteins that block IFN action (which inhibits the generation of IL-17-producing T cells).
Two specific aims are proposed: ? ? (1) Define the transcription factors that contribute to the differentiation of IL-17-producting T cells and the production of specific cytokines by these cells. Combination of cells from mice deficient in signal transducer and activator of transcription (STAT3), STAT4 or T-bet and the treatment in culture with different cytokines will be employed. ? ? (2) To investigate the function of IL-17-producing T cells in mice infected with vaccinia virus, characterizing deficient mice with altered development of IL-17-producing T cells, the effect of adoptive transfer of IL-17-producing cells and the neutralization of IL-17 with antiserum. ? ? These studies may help the development of improved vaccinia virus vaccines which may regulate the formation of IL-17-producing T cells and reduce the damaging inflammation caused by the smallpox vaccine. These investigations will define the role of IL-17-producing T cells in virus infections. ? ? ?
| Kaplan, Mark H; Glosson, Nicole L; Stritesky, Gretta L et al. (2011) STAT3-dependent IL-21 production from T helper cells regulates hematopoietic progenitor cell homeostasis. Blood 117:6198-201 |
| Yeh, Norman; Glosson, Nicole L; Wang, Nan et al. (2010) Tc17 cells are capable of mediating immunity to vaccinia virus by acquisition of a cytotoxic phenotype. J Immunol 185:2089-98 |
