Blockade of IL-10 signaling during BCG vaccination enhances and sustains Th1, Th17, and innate lymphoid IFN-γ and IL-17 responses and increases protection to Mycobacterium tuberculosis infection

Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis (Mtb), but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against Mtb infection. Early production of IL-17 in the lungs following Mtb challenge of mice previously vaccinated with Mtb peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary Mtb infection, with Il10−/− mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated antigen-specific IFN-γ and IL-17A responses, and that this regime gives significantly greater protection against aerogenic Mtb challenge in both susceptible and relatively resistant strains of mice. In Mtb-susceptible CBA/J mice, antibody blockade of IL-10R specifically during BCG vaccination resulted in additional protection against Mtb challenge of greater than 1-Log10 compared to equivalent isotype-treated controls. Protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic Mtb infection, and correlated with enhanced lung Th1 and Th17 responses, and enhanced IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2+CD3— lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis. Address correspondence and reprint requests to: Anne O’Garra [email protected] Phone: (Direct) +44-208-816-2508 Fax: +44-208-816-2564. Europe PMC Funders Group Author Manuscript J Immunol. Author manuscript; available in PMC 2013 April 15. Published in final edited form as: J Immunol. 2012 October 15; 189(8): 4079–4087. doi:10.4049/jimmunol.1201061. E uope PM C Fuders A uhor M ancripts E uope PM C Fuders A uhor M ancripts