Human memory CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader pathogen-specific responses

Stetsenko, V.; Gail, D. P.; Reba, S.; Suzart, V. G.; Sandhu, A. K.; Sette, A.; Dezfulian, M. H.; Arlehamn, C. S. L.; Carpenter, S. M.

doi:10.1101/2025.02.23.639515

bioRxiv · 10.1101/2025.02.23.639515

Human memory CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader pathogen-specific responses

Stetsenko, V.·Gail, D. P.·Reba, S.·Suzart, V. G.·Sandhu, A. K.·Sette, A.·Dezfulian, M. H.·Arlehamn, C. S. L.·Carpenter, S. M.

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Abstract

Recognition of macrophages infected with Mycobacterium tuberculosis (Mtb) is essential for CD4+ T cells to prevent tuberculosis (TB). Yet not all antigen-specific T cells recognize infected macrophages in human and murine models. Using monocyte-derived macrophages (MDMs) and autologous memory CD4+ T cells from individuals with latent Mtb infection (LTBI), we quantify T cell activation in response to infected macrophages. T cell antigen receptor (TCR) sequencing revealed >70% of unique and >90% of total Mtb-specific TCR clonotypes in stable LTBI are linked to recognition of infected macrophages, while a subset required exogenous antigen exposure, suggesting incomplete recognition. Clonotypes specific for multiple Mtb antigens and other pathogens were identified, indicating Mtb-specific and non-specific activation. Single-cell transcriptomics demonstrates Mtb-specific T cells express signature effector functions dominated by IFN{gamma}, TNF, IL-2, and GM-CSF or chemokine production and signaling. We propose TB vaccines that elicit T cells capable of recognizing infected macrophages and expressing these canonical effector functions will offer protection against TB.

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Stetsenko, V., Gail, D. P., Reba, S., Suzart, V. G., Sandhu, A. K., Sette, A., Dezfulian, M. H., Arlehamn, C. S. L., Carpenter, S. M.. 2025-02-27. Human memory CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader pathogen-specific responses. https://doi.org/10.1101/2025.02.23.639515

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