title: Diabetic mice display a delayed adaptive immune response to Mycobacterium tuberculosis.
abstract: Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB) but the defect in protective immunity responsible for this has not been defined. We previously reported that streptozotocin-induced DM impaired TB defense in mice, resulting in higher pulmonary bacterial burden, more extensive inflammation, and higher expression of several proinflammatory cytokines known to play a protective role in TB. In the current study, we tested the hypothesis that DM leads to delayed priming of adaptive immunity in the lung-draining lymph nodes (LNs) following low dose aerosol challenge with virulent Mycobacterium tuberculosis. We show that M. tuberculosis-specific IFN-gamma-producing T cells arise later in the LNs of diabetic mice than controls, with a proportionate delay in recruitment of these cells to the lung and stimulation of IFN-gamma-dependent responses. Dissemination of M. tuberculosis from lung to LNs was also delayed in diabetic mice, although they showed no defect in dendritic cell trafficking from lung to LNs after LPS stimulation. Lung leukocyte aggregates at the initial sites of M. tuberculosis infection developed later in diabetic than in nondiabetic mice, possibly related to reduced levels of leukocyte chemoattractant factors including CCL2 and CCL5 at early time points postinfection. We conclude that TB increased susceptibility in DM results from a delayed innate immune response to the presence of M. tuberculosis-infected alveolar macrophages. This in turn causes late delivery of Ag-bearing APC to the lung draining LNs and delayed priming of the adaptive immune response that is necessary to restrict M. tuberculosis replication.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Therese
authors.initials: T
authors.lastname: Vallerskog
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Martens
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D014397:Tuberculosis, Pulmonary / Q000150:complications* / Q000276:immunology* / Q000473:pathology
chemical_list: D007371:Interferon-gamma