Differential CD28 and Inducible Costimulatory Molecule Signaling Requirements for Protective CD4+T-Cell-Mediated Immunity against Genital TractChlamydia trachomatisInfection

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Abstract
Th1 cells and gamma interferon (IFN-γ) production play critical roles in protective immunity against genital tract infections byChlamydia trachomatis. Here we show that inducible costimulatory molecule (ICOS)−/−mice develop greatly augmented host resistance against chlamydial infection. Protection following a primary infection was characterized by strong Th1 immunity with enhanced CD4+T-cell-mediated IFN-γ production in the genital tract and high expression of T-bet in the draining para-aortic lymph node. This Th1 dominance was associated with low expression of interleukin 10 (IL-10) mRNA in the uteruses of protected ICOS−/−mice. By contrast, CD28−/−mice were severely impaired in their adaptive immune response, demonstrating a lack of CD4+T cells and IFN-γ in the genital tract, with a substantial delay in bacterial elimination compared to that seen in wild-type (WT) mice. Upon reinfection, WT mice exhibited a transient local infection with evidence of regulatory T-cell (Treg)/Foxp3 mRNA and a more balanced Th1 and Th2 response in the genital tract than ICOS−/−mice, whereas 90% of the latter mice developed sterile immunity, poor expression of local Treg/Foxp3 mRNA, and macroscopic signs of enhanced local immunopathology. Therefore, different requirements for CD28 signaling and ICOS signaling clearly apply to host protection against a genital tract infection byC. trachomatis. Whereas, CD28 signaling is critical, ICOS appears to be dispensable and can have a dampening effect on Th1 development by driving Th2 immunity and anti-inflammation through IL-10 production and promotion of the Foxp3+Treg populations in the genital tract. Both the CD28-deficient and the ICOS-deficient mice demonstrated poor specific antibody production, supporting the fact that antibodies are not needed for protection against genital tract chlamydial infections.