CD4+ T Cells Are as Protective as CD8+ T Cells against Rickettsia typhi Infection by Activating Macrophage Bactericidal Activity

Abstract

Rickettsia typhi is an intracellular bacterium that causes endemic typhus, a febrile disease that can be fatal due to complications including pneumonia, hepatitis and meningoencephalitis, the latter being a regular outcome in T and B cell-deficient C57BL/6 RAG1-/- mice upon Rickettsia typhi infection. Here, we show that CD4+ TH1 cells that are generated in C57BL/6 mice upon R. typhi infection are as protective as cytotoxic CD8+ T cells. CD4+- as well as CD8+-deficient C57BL/6 survived the infection without showing symptoms of disease at any point in time. Moreover, adoptively transferred CD8+ and CD4+ immune T cells entered the CNS of C57BL/6 RAG1-/- mice with advanced infection and both eradicated the bacteria. However, immune CD4+ T cells protected only approximately 60% of the animals from death. They induced the expression of iNOS in infiltrating macrophages as well as in resident microglia in the CNS which can contribute to bacterial killing but also accelerate pathology. In vitro immune CD4+ T cells inhibited bacterial growth in infected macrophages which was in part mediated by the release of IFNγ. Collectively, our data demonstrate that CD4+ T cells are as protective as CD8+ T cells against R. typhi, provided that CD4+ TH1 effector cells are present in time to support bactericidal activity of phagocytes via the release of IFNγ and other factors. With regard to vaccination against TG Rickettsiae, our findings suggest that the induction of CD4+ TH1 effector cells is sufficient for protection.

Immune response against rickettsiae: lessons from murine infection models

“…The same has been observed upon the infection of peritoneal MΦ from C3H/HeN mice with R. typhi that additionally induced the release of TGFβ [ 17 ]. In other studies, however, bone marrow-derived MΦ from BALB/c and C57BL/6 mice neither produced cytokines nor nitric oxide (NO) upon infection with R. typhi, but exclusively upregulated MHCI and CD80 on the cell surface [ 40 , 47 ]. Although there may be differences in the reactivity of MΦ from different mouse strains and also between peritoneal and bone marrow-derived MΦ, these observations argue against classical activation of MΦ by R. typhi which is usually mediated by pathogen recognition via pathogen recognition receptors such as TLR.…”

“…The majority of activated MΦ and neutrophils that express iNOS in R. typhi -infected mice does not harbor the bacteria [ 40 ]. Together with the finding that R. typhi does not activate bone marrow-derived MΦ from BALB/c and C57BL/6 mice in vitro in a classical manner [ 40 , 47 ], a role of TLR in the activation of innate immune response by TG rickettsiae such as R. typhi is questioned. It has been suggested that activation of MΦ in the infection with R. typhi in vivo is mediated by indirect mechanisms such as the release of endogenous danger signals by damaged cells rather than direct recognition of the bacteria [ 40 ].…”

“…The peak response is observed on day 10 post infection [ 46 ]. Similarly, CD8 + T cells from R. typhi -infected C57BL/6 [ 47 ] and BALB/c mice [ 45 ] express enhanced levels of Granzyme B, demonstrating cytotoxic properties, and release IFNγ. Both Granzyme B and IFNγ expression peak on day 7 post infection in both strains of mice [ 45 , 47 ].…”

“… − [ 46 ] R. typhi s.c., i.v. − Mild hepatitis, pneumonia yes [ 33 , 47 ]+Osterloh unpubl. O. tsutsugamushi i.p.…”

“… − [ 43 ] MHCI −/− R. australis i.v. +++ Encephalitis [ 46 ] R. typhi s.c. − [ 47 ] MHCII −/− R. typhi s.c. − [ 47 ] RAG2 −/− R. conorii i.v. − (?)…”