Dynamics of peripheral T cell phenotype and function during tuberculosis disease progression

Background Antigen-specific CD4 T cells are essential but not sufficient for controlling Mycobacterium tuberculosis ( Mtb ) infection. We characterized changes in Mtb- specific CD4, and CD8 and γδ T cell frequencies and phenotypes during tuberculosis progression. Methods Mtb-infected adolescents, who remained healthy or progressed to tuberculosis, were followed longitudinally. Bulk and Mtb- specific T cells were profiled by intracellular cytokine staining and mass cytometry. Systemic inflammation was profiled by blood transcriptomics and proteomics. Features associated with disease progression or systemic inflammation were identified by mixed-effects modelling. Results Among many phenotypes of bulk CD4, CD8 and γδ T cells, only CD4 T cell activation (HLA-DR+) increased significantly during progression. However, levels of systemic inflammatory biomarkers of tuberculosis were strongly associated with changes in many phenotypic subsets of CD4, CD8 and γδ T cells. Similarly, among hundreds of Mtb- specific functional and phenotypic CD4 and CD8 T cell subsets, only two early-differentiated CD4 subsets (IL-2 ⁺ TNF ⁺ CD7 ⁺ CD27 ⁺ and IFNγ ⁺ IL-2 ⁺ TNF ⁺ CD7 ⁺ CD27 ⁺ ) significantly decreased, while Mtb -specific CD4 T cell activation increased during progression. These changes correlated with systemic inflammation. Conclusion Our findings suggest that peripheral blood frequencies and functions of Mtb-specific T cell subsets do not associate with tuberculosis progression, but that inflammation drives marked changes in T cell activation and differentiation.