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Differential CD28 and Inducible Costimulatory Molecule Signaling Requirements for Protective CD4⁺ T-Cell-Mediated Immunity against Genital Tract Chlamydia trachomatis Infection

Ellen Marks,¹ Martina Verolin,^2, Anneli Stensson,¹ and Nils Lycke^1*

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, Gothenburg University, Box 435, 40530 Gothenburg, Sweden,¹ Department of Clinical Immunology, Gothenburg University, Box 435, 40530 Gothenburg, Sweden²

Received 30 March 2007/ Returned for modification 8 May 2007/ Accepted 3 July 2007

Th1 cells and gamma interferon (IFN-) production play critical roles in protective immunity against genital tract infections by Chlamydia 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- 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- 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 by 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 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.

Published ahead of print on 16 July 2007.

Editor: R. P. Morrison

Formerly Martina Johansson.