title: Host defense and recruitment of Foxp3⁺ T regulatory cells to the lungs in chronic Mycobacterium tuberculosis infection requires toll-like receptor 2.
abstract: Acute resistance to low dose M. tuberculosis (Mtb) infection is not dependent on Toll-like receptor (TLR) 2. However, whether TLR2 contributes to resistance in chronic Mtb infection has remained uncertain. Here we report that, following low dose aerosol infection with Mtb, mice lacking TLR2 (TLR2KO), in comparison with wild type (WT) mice, exhibit enhanced cellular infiltration and inflammation in the lungs, and fail to stably control bacterial burden during chronic infection. IFNγ and IL-17 was expressed at equivalent levels in the two groups; however, the characteristic accumulation of Foxp3⁺ T regulatory cells (Tregs) in pulmonary granulomas was significantly reduced in TLR2KO mice. Nonetheless, this reduction in Tregs was independent of whether Tregs expressed TLR2 or not. To directly link the reduced number of Tregs to the increased inflammation present in the TLR2KO mice, we used a macrophage adoptive transfer model. At seven weeks post-Mtb infection, TLR2KO mice, which were adoptively transferred with WT macrophages, displayed enhanced accumulation of Tregs in the lungs and a concomitant reduction in inflammation in contrast with control mice that received TLR2KO macrophages. However, the pulmonary bacterial burden between the two groups remained similar indicating that TLR2's role in modulating immunopathology is functionally distinct from its role in restricting Mtb growth in chronic infection. Together, these findings unequivocally demonstrate that TLR2 contributes to host resistance against chronic Mtb infection and reveal a novel role for TLR2 in mediating the recruitment of Foxp3⁺ Tregs to the lungs to control inflammation.
authors.affiliation: UMDNJ-New Jersey Medical School, Department of Medicine, Centre for Emerging Pathogens Newark, Newark, New Jersey, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: McBride
authors.forename: Jill
authors.initials: J
authors.lastname: Konowich
authors.forename: Padmini
authors.initials: P
authors.lastname: Salgame
mesh_terms: D000818:Animals; D002908:Chronic Disease; D051858:Forkhead Transcription Factors / Q000276:immunology; D007113:Immunity, Innate; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2