Fig 1. Immune response against rickettsiae.

CD8⁺ cytotoxic T cells play the most important role against most rickettsiae and can directly kill infected cells. Apart from the cytotoxic activity, CD8⁺ T cells also release IFNγ. The cytotoxic activity of CD8⁺ T cells plays a dominant role in defense against SFG rickettsiae and Orienta, while the release of IFNγ seems to be more important in long-term control of TG rickettsiae (A). IFNγ, which is released at high amounts by CD4⁺ T_H1 cells in addition to TNFα, acts against rickettsiae by activating antimicrobial mechanisms, e.g., NO production in MΦ and other infected cells (B). In the absence of IFNγ, CD4⁺ T cells develop into T_H17 cells that produce IL-17, IL-22, and TNFα. These cells can also protect against rickettsial infections by acting on MΦ via IL-17 and TNFα that induce the production of NO and the release of chemokines that attract neutrophils (PMNs). IL-22, in addition to IL-17 and TNFα, also induces the production of NO, antimicrobial peptides, and other microbicidal mechanisms in infected tissue cells. In this way, T_H17 cells are capable to eliminate the bacteria. The combined release of TNFα and IL-17, however, exerts pathological effects (C). The production of specific high-affinity antibodies by B cells depends on T cell help. Specific antibodies are produced late in the infection with rickettsiae and are considered to play a minor role in primary defense. Antibodies can contribute to defense most likely by opsonizing the bacteria for the uptake and destruction by MΦ or the activation of complement to mediate direct bacterial killing (D). The most promising way to achieve immunity against rickettsiae by a vaccine is the induction of specific cytotoxic CD8⁺ and/or IFNγ-producing CD4⁺ T_H1 cells, in best case in addition to antibody-producing B cells. IFNγ, interferon gamma; IL-17, interleukin 17; IL-22, interleukin 22; iNOS, inducible nitric oxide synthase; MΦ, monocytes/macrophages; NO, nitric oxide; PMN, polymorphonuclear neutrophils; ROS, reactive oxygen species; SFG, spotted fever group; TG, typhus group; TNFα, tumor necrosis factor alpha.