TLR2 deficiency by compromising p19 (IL-23) expression limits T helper 17 cell responses to Mycobacterium tuberculosis

The authors are grateful to Drs. Manuel Teixeira da Silva, Fernando Rodrigues, Margarida Correia-Neves and Paul S. Redford for critically reading this manuscript and thank the personnel at the ICVS animal house facility for excellent animal husbandry.CD4+ Th1 cells producing IFN-γ are of extreme importance in controlling infections by Mycobacterium tuberculosis both in mice and in men. In addition to IFN-γ-producing T cells, IL-17-producing T cells (Th17) have been observed during mycobacterial infections. Nevertheless, their contribution for the host immune response to mycobacteria as well as the signals triggering M. tuberculosis -specific Th17 cell differentiation and maintenance are not fully understood. We show that signaling via Toll-like receptor (TLR) 2 has a major impact on the regulation of p19 (IL-23) expression in response to M. tuberculosis and therefore on the establishment of Th17 cell responses to M. tuberculosis infection. Diminished Th17 responses in the lung of M. tuberculosis -infected TLR2-deficient animals were not caused by defective cell differentiation in the draining lymph node (LN) but rather by reduced maintenance at the site of infection. Consistent with the decreased numbers of Th17 cells in the lungs of infected TLR2-deficient animals, we observed reduced expression of CXCL9, CXCL10 and CXCL11, chemokines involved in recall responses to M. tuberculosis. Our data provides insights into the TLR2 role in infection with M. tuberculosis, with implications in pathophysiology of the disease and vaccine design.Fundação para a Ciência e Tecnologia, Portugal (Project Grants PTDC/SAU/70895/2006 to AGC and PTDC/BIA-BCM/102776/2008 to MS; and Personal Grants SRFH/BD/33034/2006 to MTC; SFRH/BPD/3306/2007 to AC; SFRH/BD/35981/2007 to JC; SFRH/BI/33456/2008 to CS and PTDC/SAU-MII/70895/2006 to DRP) and by the Health Service of Fundação Calouste Gulbenkian. MS is a Ciência 2007 Fellow