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 TH1 and TH17 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.