A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.44-11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected cells, thereby focusing CD8 T cells on nonprotective antigens. Here, we leverage naturally occurring polymorphisms in esxH, which frequently occur in lineage 1 strains, to test this decoy hypothesis . Using the clinical isolate 667, which contains an EsxHA10T polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxHA10T and Erd.EsxHWT strains, we prove that this polymorphism alters the hierarchy of immunodominant CD8 T cell responses. Our data are best explained by immunodomination, a mechanism by which competition for APC leads to dominant responses suppressing subdominant responses. These results were surprising as the variant epitope can bind to H2-Kb and is recognized by TB10.4-specific CD8 T cells. The dramatic change in TB10.4-specific CD8 responses resulted from increased proteolytic degradation of A10T variant, which destroyed the TB10.44-11epitope. Importantly, this polymorphism affected T cell priming and recognition of infected cells. These data support a model in which nonprotective CD8 T cells become immunodominant and suppress subdominant responses. Thus, polymorphisms between clinical Mtb strains, and BCG or H37Rv sequence-based vaccines could lead to a mismatch between T cells that are primed by vaccines and the epitopes presented by infected cells. Reprograming host immune responses should be considered in the future design of vaccines

Emissions from open biomass burning in India: Integrating the inventory approach with high-resolution Moderate Resolution Imaging Spectroradiometer (MODIS) active-fire and land cover data

[ 1] Climatological mean estimates of forest burning and crop waste burning based on broad assumptions of the amounts burned have so far been used for India in global inventories. Here we estimate open biomass burning representative of 1995 - 2000 from forests using burned area and biomass density specific for Indian ecosystems and crop waste burning as a balance between generation and known uses as fuel and fodder. High-resolution satellite data of active fires and land cover classification from MODIS, both on a scale of 1 km x 1 km, were used to capture the seasonal variability of forest and crop waste burning and in conjunction with field reporting. Correspondence in satellite-detected fire cycles with harvest season was used to identify types crop waste burned in different regions. The fire season in forest areas was from February to May, and that in croplands varied with geographical location, with peaks in April and October, corresponding to the two major harvest seasons. Spatial variability in amount of forest biomass burned differed from corresponding forest fire counts with biomass burned being largest in central India but fire frequency being highest in the east-northeast. Unutilized crop waste and MODIS cropland fires were predominant in the western Indo-Gangetic plain. However, the amounts of unutilized crop waste in the four regions were not strictly proportional to the fire counts. Fraction crop waste burned in fields ranged from 18 to 30% on an all-India basis and had a strong regional variation. Open burning contributes importantly ( about 25%) to black carbon, organic matter, and carbon monoxide emissions, a smaller amount ( 9 - 13%) to PM2.5 ( particulate mass in particles smaller than 2.5 micron diameter) and CO2 emissions, and negligibly to SO2 emissions (1%). However, it cannot explain a large "missing source'' of BC or CO from India