T cell IFNγ production is restricted within pulmonary tuberculosis granulomas

Abstract

Listen

Translate article

Abstract The direct interaction between CD4 T cells and Mycobacterium tuberculosis (Mtb) infected cells presenting their cognate antigen on MHCII is crucial for optimal bacterial control. Using quantitative imaging (QIM) and a physiologic ultra-low dose (ULD) Mtb infection in mice to visualize this interaction, we have found that while T cell receptor (TCR) signaling in CD4 T cells occurs throughout Mtb-infected lungs, IFNγ production is impaired near infected cells. To examine the antigen-specificity of this observation, we co-transferred Th1-polarized Mtb ESAT-6-specific CD4 cells (C7) and OVA-specific (OTII) CD4 T cells into mice 35 days post ULD Mtb infection. The next day, lungs were harvested for phenotypic and spatial analysis of TCR signaling (using IRF4) and IFNγ production. QIM revealed TCR signaling and IFNγ production in Mtb-specific T cells, but minimal TCR signaling and IFNγ production in control T cells with irrelevant specificity for OVA. Positioning data showed that TCR recognition of Mtb ESAT-6 occurred throughout the lung, including within the center of the granuloma, where most Mtb bacilli are observed. Despite this, only 1–2% of ESAT-6-specific T cells within the granuloma produced IFNγ, whereas 10–15% produced IFNγ outside the granuloma, where Mtb bacilli are sparse. Thus, T cell production of IFNγ is restricted at the site of Mtb infection within the granuloma, despite ongoing TCR signaling at this location. These findings may help explain why IFNγ-producing T cells may be more efficient at preventing extrapulmonary dissemination than in controlling Mtb within the lung. Understanding the mechanisms regulating this local immunosuppression may yield new strategies for vaccine and immunotherapeutic development.