TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG

Toll-like receptor (TLR) proteins me- diate cellular activation by microbes and microbial products. To delineate the role of TLR proteins in the development of host immune responses against mycobacteria, wild-type and TLR-deficient mice were infected with nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin (BCG). Two weeks after intraperitoneal challenge with BCG, few ba- cilli were present in the lungs of wild-type and TLR4 / mice, whereas bacterial loads were ten- fold higher in the lungs of infected TLR2 / mice. BCG challenge in vitro strongly induced proinflam- matory cytokine secretion by macrophages from wild-type and TLR4 / mice but not by TLR2 / macrophages. In contrast, intracellular uptake, in- tracellular bacterial growth, and suppression of intracellular bacterial growth in vitro by inter- feron- (IFN-) were similar in macrophages from all three mouse strains, suggesting that BCG growth in the lungs of TLR2 / mice was a conse- quence of defective adaptive immunity. Antigenic stimulation of splenocytes from infected wild-type and TLR4 / mice induced T cell proliferation in vitro, whereas T cells from TLR2 / mice failed to proliferate. Unexpectedly, activated CD4 T cells from both TLR-deficient mouse strains secreted little IFN- in vitro compared with control T cells. A role for TLR4 in the control of bacterial growth and IFN- production in vivo was observed only when mice were infected with higher numbers of BCG. Thus, TLR2 and TLR4 appear to regulate distinct aspects of the host immune response against BCG. J. Leukoc. Biol. 74: 277-286; 2003.