Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Abstract

The obligately intracellular bacteria Rickettsia infect endothelial cells and cause systemic febrile diseases that are potentially lethal. No vaccines are currently available and current knowledge of the effective immune response is limited. Natural and experimental rickettsial infections provide strong and cross-protective cellular immunity if the infected individual survives the acute infection. Although resistance to rickettsial infections is attributed to the induction of antigen-specific T cells, particularly CD8+ T cells, the identification and validation of correlates of protective cellular immunity against rickettsial infections, an important step towards vaccine validation, remains a gap in this field. Here, we show that after a primary challenge with Rickettsia typhi in the C3H mouse model, the peak of anti-Rickettsia CD8+ T cell-mediated responses occurs 7 days post-infection (dpi), which coincides with the beginning of rickettsial clearance. At this time point, both effector-type and memory-type CD8+ T cells are present, suggesting that 7 dpi is a valid time point for the assessment of CD8+ T cell responses of mice previously immunized with protective antigens. Based on our results, we suggest four correlates of cellular protection for the assessment of protective rickettsial antigens: 1) production of IFN-γ by antigen experienced CD3+CD8+CD44high cells, 2) production of Granzyme B by CD27lowCD43low antigen-experienced CD8+ T cells, 3) generation of memory-type CD8+ T cells [Memory Precursor Effector Cells (MPECs), as well as CD127highCD43low, and CD27highCD43low CD8+ T cells], and 4) generation of effector-like memory CD8+ T cells (CD27lowCD43low). We propose that these correlates could be useful for the general assessment of the quality of the CD8+ T cell immune response induced by novel antigens with potential use in a vaccine against Rickettsia.

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

“…Both the CD4 + and CD8 + T cell response peaked on day 7 post infection and then declined as it was also observed in R . typhi -infected C57BL/6 mice [ 19 ]and C3H/HeN mice [ 40 ]. Surprisingly, in BALB/c mice activated T cells were again detectable late in infection at day 35.…”

Case Report: Renal Failure due to Focal Segmental Glomerulosclerosis in a Patient with Murine Typhus

“…15 As documented in both humans and animal models, infection with R. typhi is associated with elevated IFN-γ. 20,21 The mean value of IFN-γ in those with murine typhus has been reported to be approximately 600 pg/mL (during the acute phase of illness). 21 To compare with two other prevalent undifferentiated febrile illnesses, dengue and malaria, mean IFN-γ levels have been reported to be approximately 25 pg/mL and 231 pg/mL, respectively.…”

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

“…In line with these findings KLRG1 was expressed on CD8 + T cells with similar kinetics in C3H/HeN mice upon R . typhi infection [72]. Furthermore, enhanced cytotoxic CD8 + T cell responses were observed in R .…”