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Infect. Immun. doi:10.1128/IAI.00465-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Differential CD28 and ICOS signaling requirements for protective CD4⁺ T cell mediated immunity against genital tract Chlamydia trachomatis infection

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, Gothenburg University, Box 435, 40530 Gothenburg, Sweden; Department of Clinical Immunology, Gothenburg University, Box 435, 40530 Gothenburg, Sweden

^* To whom correspondence should be addressed. Email: nils.lycke{at}microbio.gu.se.

	Abstract

Th1 cells and IFN- production play critical roles in protective immunity against genital tract infections with C. trachomatis. Here we show that 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- production in the genital tract and high expression of T-bet in the draining paraaortic lymph node (PALN). This Th1 dominance was associated with low expression of IL-10 mRNA in the uterus of protected ICOS^-/- mice. By contrast, CD28^-/- mice were severely impaired in their adaptive immune response, demonstrating lack of CD4⁺ T cells and IFN- in the genital tract with a substantial delay in bacterial elimination compared to that seen in WT mice. Upon reinfection WT mice exhibited a transient local infection with evidence of 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 local Treg/Foxp3 mRNA and macroscopic signs of enhanced local immunopathology. Therefore, differential requirements for CD28- and ICOS-signaling clearly apply to host protection against a genital tract infection with C. 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 promoting Foxp3⁺ Treg populations in the genital tract. Both CD28- and ICOS-deficient mice demonstrated poor specific antibody production, supporting that antibodies are not needed for protection against genital tract chlamydial infections.

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