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.sub.H1 and T.sub.H17 cytokines in protection and pathology

• Published in: PLoS neglected tropical diseases Vol. 11; no. 2
• Main Authors: Moderzynski, Kristin, Heine, Liza, Rauch, Jessica, Papp, Stefanie, Kuehl, Svenja, Richardt, Ulricke, Fleischer, Bernhard, Osterloh, Anke
• Format: Journal Article
• Language: English
• Published: Public Library of Science 21-02-2017
• Subjects: Analysis; Cytokines; Endemic diseases; Health aspects; Prevention; Rickettsiae; T cells; Germany
• ISSN: 1935-2727
• DOI: 10.1371/journal.pntd.0005404

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.sup.+ T.sub.H 1 and cytotoxic CD8.sup.+ T cells both of which are sporadically reactivated in persistent infection. Either adoptively transferred CD8.sup.+ or CD4.sup.+ T cells protected R. typhi-infected CB17 SCID mice from death and provided long-term control. CD8.sup.+ T cells lacking either IFN[gamma] or Perforin were still protective, demonstrating that the cytotoxic function of CD8.sup.+ T cells is not essential for protection. Immune wild-type CD4.sup.+ T cells produced high amounts of IFN[gamma], induced the release of nitric oxide in R. typhi-infected macrophages and inhibited bacterial growth in vitro via IFN[gamma] and TNF[alpha]. However, adoptive transfer of CD4.sup.+ IFN[gamma].sup.-/- T cells still protected 30-90% of R. typhi-infected CB17 SCID mice. These cells acquired a T.sub.H 17 phenotype, producing high amounts of IL-17A and IL-22 in addition to TNF[alpha], and inhibited bacterial growth in vitro. Surprisingly, the neutralization of either TNF[alpha] or IL-17A in CD4.sup.+ IFN[gamma].sup.-/- 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.sup.+ T.sub.H 1 cells are clearly efficient in protection against R. typhi, CD4.sup.+ T.sub.H 17 cells are similarly protective if the harmful effects of combined production of TNF[alpha] and IL-17A can be inhibited.