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Infection and Immunity, January 2006, p. 673-681, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.673-681.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CD4⁺-T-Cell Effector Functions and Costimulatory Requirements Essential for Surviving Mucosal Infection with Citrobacter rodentium

Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Medicine,¹ Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115²

Received 14 June 2005/ Returned for modification 21 September 2005/ Accepted 24 October 2005

Citrobacter rodentium causes an attaching and effacing infection of the mouse colon. Surprisingly, protective adaptive immunity against this mucosal pathogen requires a systemic T-cell-dependent antibody response. To define CD4⁺ T-cell effector functions promoting this systemic defense of infected epithelial surfaces, studies were undertaken in weaning-age mice lacking costimulatory molecules CD28 or CD40L or cytokines gamma interferon (IFN-) or interleukin-4 (IL-4). Adoptive transfer of CD4⁺ T cells from wild-type, CD28^–/–, CD40L^–/–, or IFN-^–/– donors to CD4^–/– recipients delineated functions of these CD4⁺ T-cell-expressed molecules on the outcome of infection. Wild-type and IL-4^–/– mice successfully resolved infection, while 70% of IFN-^–/– mice survived. In contrast, all CD28^–/– mice succumbed during acute infection. While fewer than half of CD40L^–/– mice succumbed acutely, surviving mice failed to clear infection, resulting in progressive mucosal destruction, polymicrobial sepsis, and death 1 to 2 weeks later than in CD28^–/– mice. Downstream of CD28-mediated effects, CD4⁺ T-cell-expressed CD40L proved essential for generating acute pathogen-specific immunoglobulin M (IgM) and early IgG, which reduced pathogen burdens. However, deficiency of CD4⁺ T-cell-expressed IFN- did not adversely impact survival or development of protective antibody in adoptively transferred CD4^–/– recipients, though it impacted Th1 antibody responses. These findings demonstrate that CD4⁺ T-cell-expressed CD40L promotes the rapid production of protective systemic antibody during acute infection, while deficiencies of IL-4 or of CD4⁺ T-cell-expressed IFN- can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces.

Editor: A. D. O'Brien

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