Cytotoxic effector functions of T cells are not required for protective immunity against fatal Rickettsia typhi infection in a murine model of infection: Role of T(H)1 and T(H)17 cytokines in protection and pathology

Endemic typhus caused by Rickettsia (R.) typhi is an emerging febrile disease that can be fatal due to multiple organ pathology. Here we analyzed the requirements for protection against R. typhi by T cells in the CB17 SCID model of infection. BALB/c wild-type mice generate CD4(+) T(H)1 and cytotoxic CD8(+) T cells both of which are sporadically reactivated in persistent infection. Either adoptively transferred CD8(+) or CD4(+) T cells protected R. typhi-infected CB17 SCID mice from death and provided long-term control. CD8(+) T cells lacking either IFNγ or Perforin were still protective, demonstrating that the cytotoxic function of CD8(+) T cells is not essential for protection. Immune wild-type CD4(+) T cells produced high amounts of IFNγ, induced the release of nitric oxide in R. typhi-infected macrophages and inhibited bacterial growth in vitro via IFNγ and TNFα. However, adoptive transfer of CD4(+)IFNγ(-/-) T cells still protected 30–90% of R. typhi-infected CB17 SCID mice. These cells acquired a T(H)17 phenotype, producing high amounts of IL-17A and IL-22 in addition to TNFα, and inhibited bacterial growth in vitro. Surprisingly, the neutralization of either TNFα or IL-17A in CD4(+)IFNγ(-/-) T cell recipient mice did not alter bacterial elimination by these cells in vivo, led to faster recovery and enhanced survival compared to isotype-treated animals. Thus, collectively these data show that although CD4(+) T(H)1 cells are clearly efficient in protection against R. typhi, CD4(+) T(H)17 cells are similarly protective if the harmful effects of combined production of TNFα and IL-17A can be inhibited.