title: Inhibition of T cells provides protection against early invasive pneumococcal disease.
abstract: Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4(+) T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II-deficient mice, which lack CD4(+) T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II-deficient mice, antibody-mediated depletion of CD4(+) T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4(+) T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: LeMessurier
authors.forename: Hans
authors.initials: H
authors.lastname: Häcker
authors.forename: Elaine
authors.initials: E
authors.lastname: Tuomanen
authors.forename: Vanessa
authors.initials: V
authors.lastname: Redecke
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018925:Chemokines / Q000097:blood / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000502:physiology; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011008:Pneumococcal Infections / Q000276:immunology*; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D016572:Cyclosporine