Divergent Functions of TLR2 on Hematopoietic and Nonhematopoietic Cells during Chronic Mycobacterium tuberculosis Infection.

We have reported that TLR2 is crucial for host resistance against chronic Mycobacterium tuberculosis infection; however, which cell types are key players in this response remain unknown. This led us to decipher the relative contribution of TLR2 on nonhematopoietic and hematopoietic cells in resistance against chronic M. tuberculosis infection in mice infected with M. tuberculosis Erdman. Consistent with our previous report, at 8 wk of infection, TLR2 knockout (TLR2KO)→TLR2KO bone marrow chimeric mice exhibited increased bacterial burden, disorganized accumulation of lymphocytes and mononuclear cells, and extensive pulmonary immunopathology compared with wild-type (WT)→WT chimeric mice. Bacterial burden and pulmonary immunopathology of chimeric mice lacking TLR2 in the hematopoietic compartment (TLR2KO→WT) was comparable to TLR2KO mice. In contrast, chimeric mice deficient in TLR2 in the nonhematopoietic compartment (WT→TLR2KO) exhibited a marked attenuation in granulomatous inflammation compared with WT mice. Although the latter mice did not exhibit improved pulmonary bacterial control, significant reductions in bacterial burden in the draining lymph nodes, spleen, and liver were observed. These findings establish that the TLR2-mediated hematopoietic response promotes stable control of pulmonary bacterial burden and granuloma integrity, whereas TLR2 signaling on nonhematopoietic cells may partly facilitate granulomatous inflammation and bacterial dissemination.

Host defense and recruitment of Foxp3⁺ T regulatory cells to the lungs in chronic Mycobacterium tuberculosis infection requires toll-like receptor 2.

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.