Cellular and molecular heterogeneity of lung resident T memory cells in protective immunity 2819

Abstract Description Lung TRMs are essential defenders against respiratory reinfection, although the mechanisms regarding their heterogeneity and protective activities remain incompletely understood. The difficulties in manipulating polyclonal endogenous TRMs hinder exploring their natural responses. Although monoclonal TCR transgenic T cells are used, the diverse antigen repertoire during infection raises concerns about the ability of monoclonal TRMs to accurately mirror natural TRM responses against different antigens. By analyzing lung TRM scRNA-seq data from influenza infected mice, we observed two endogenous polyclonal TRM populations: one with effector T cells characteristics (TRM-EFF); and the other upregulates T memory cell features (TRM-MEM). Our data suggested epitope-specificity of the two populations, with over 90% of nucleoprotein specific TRMs showing TRM-EFF features, while TRM-MEM predominantly reacts to polymerase. To explore the mechanisms controlling heterogeneity, we utilized the influenza that has lower antigen dose. We found that the low antigen led to diminished TRM-EFF cell counts and identifications, suggesting that initial antigen dose determine TRM heterogeneity. TRM-EFF exhibits fast expansion during reinfection compared to TRM-MEM, indicating its potential for rapid protection. Taken together, our results provide mechanistic insight into the fate decision and functional heterogeneity of TRMs, with implications for enhancing protection against respiratory infection. Topic Categories Mucosal and Regional Immunology (MUC)