CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro and in vivo.
Although IFN-gamma is necessary for survival of Mycobacterium tuberculosis infection in people and animal models, it may not be sufficient to clear the infection, and IFN-gamma is not a reliable correlate of protection. To determine whether IFN-gamma-independent mechanisms of immunity exist, we developed a murine ex vivo culture system that directly evaluates the ability of splenic or lung lymphocytes to control the growth of M. tuberculosis within infected macrophages, and that models in vivo immunity to tuberculosis. Surprisingly, CD4(+) T cells controlled >90% of intracellular M. tuberculosis growth in the complete absence of IFN-gamma stimulation of macrophages, via a NO-dependent mechanism. Furthermore, bacillus Calmette-Guerin-vaccinated IFN-gamma-deficient mice exhibited significant protection against M. tuberculosis challenge that was lost upon depletion of CD4(+) T cells. These findings demonstrate that CD4(+) T cells possess IFN-gamma-independent mechanisms that can limit the growth of an intracellular pathogen and are dominant in secondary responses to M. tuberculosis.
Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research/Food and Drug Administration, Rockville, MD 20852, USA. cowley@cber.fda.gov
Siobhán C
SC
Cowley
Karen L
KL
Elkins
D000280:Administration, Inhalation; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007106:Immune Sera / Q000494:pharmacology; D007117:Immunization, Secondary; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality
D001500:BCG Vaccine; D016207:Cytokines; D007106:Immune Sera; D009569:Nitric Oxide; D007371:Interferon-gamma