title: CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium.
abstract: 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-gamma) or interleukin-4 (IL-4). Adoptive transfer of CD4+ T cells from wild-type, CD28(-/-), CD40L(-/-), or IFN-gamma(-/-) 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-gamma(-/-) 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-gamma 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-gamma can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces.
authors.affiliation: 4226-EBRC, Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. lbry@partners.org
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
authors.forename: Manfred
authors.initials: M
authors.lastname: Brigl
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000502:physiology; D018106:CD28 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics; D044082:Citrobacter rodentium / Q000276:immunology*; D003106:Colon / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D007371:Interferon-gamma / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018805:Sepsis / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D018106:CD28 Antigens; D023201:CD40 Ligand; D007371:Interferon-gamma