Human memory CD4+ T cells recognize non-infected macrophage bystanders exposed to Mycobacterium tuberculosis-infected cells
- 1Case Western Reserve University and University Hospitals Cleveland Medical Center
Abstract
Control of Mycobacterium tuberculosis (Mtb) infection requires CD4+ T cell recognition of infected macrophages. However, T cells also colocalize with non-infected macrophages in granulomas. We investigated whether these bystander macrophages present Mtb antigens and shape human CD4+ T cell responses. Using ex vivo co-culture systems, non-infected monocyte-derived macrophages (MDMs) were exposed to Mtb-infected MDMs or infection-conditioned supernatants before co-incubation with autologous memory CD4+ T cells from individuals with latent Mtb infection (LTBI). Bystander macrophages activated memory CD4+ T cells through MHC-II-dependent antigen presentation. Single-cell T cell receptor (TCR) sequencing and TCR-transduced reporter cell lines identified Mtb-specific clonotypes recognizing both infected and bystander macrophages, as well as clonotypes preferentially recognizing infected cells. Strikingly, a subset of TCRs recognized infected but not bystander macrophages. Antigen transfer occurred through soluble Mtb proteins rather than extracellular vesicles. Compared with responses to infected macrophages, bystander macrophages induced attenuated effector responses. These findings reveal antigen-specific recognition of bystander macrophages and suggest that antigens preferentially presented by infected cells may inform TB vaccine design.
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BibTeX
@misc{suzart2026human,
title = {{Human memory CD4+ T cells recognize non-infected macrophage bystanders exposed to Mycobacterium tuberculosis-infected cells}},
author = {V. G. Suzart and R. Schauner and S. M. Reba and D. P. Gail and G. Swarbrick and D. M. Lewinsohn and D. A. Lewinsohn and B. Lepe and B. D. Bryson and S. M. Behar and C. M. Sassetti and M. L. Freeman and W. H. Boom and C. V. Harding and S. M. Carpenter},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752467},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752467v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Human memory CD4+ T cells recognize non-infected macrophage bystanders exposed to Mycobacterium tuberculosis-infected cells
AU - V. G. Suzart
AU - R. Schauner
AU - S. M. Reba
AU - D. P. Gail
AU - G. Swarbrick
AU - D. M. Lewinsohn
AU - D. A. Lewinsohn
AU - B. Lepe
AU - B. D. Bryson
AU - S. M. Behar
AU - C. M. Sassetti
AU - M. L. Freeman
AU - W. H. Boom
AU - C. V. Harding
AU - S. M. Carpenter
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752467
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752467v1
AB - Control of Mycobacterium tuberculosis (Mtb) infection requires CD4+ T cell recognition of infected macrophages. However, T cells also colocalize with non-infected macrophages in granulomas. We investigated whether these bystander macrophages present Mtb antigens and shape human CD4+ T cell responses. Using ex vivo co-culture systems, non-infected monocyte-derived macrophages (MDMs) were exposed to Mtb-infected MDMs or infection-conditioned supernatants before co-incubation with autologous memory CD4+ T cells from individuals with latent Mtb infection (LTBI). Bystander macrophages activated memory CD4+ T cells through MHC-II-dependent antigen presentation. Single-cell T cell receptor (TCR) sequencing and TCR-transduced reporter cell lines identified Mtb-specific clonotypes recognizing both infected and bystander macrophages, as well as clonotypes preferentially recognizing infected cells. Strikingly, a subset of TCRs recognized infected but not bystander macrophages. Antigen transfer occurred through soluble Mtb proteins rather than extracellular vesicles. Compared with responses to infected macrophages, bystander macrophages induced attenuated effector responses. These findings reveal antigen-specific recognition of bystander macrophages and suggest that antigens preferentially presented by infected cells may inform TB vaccine design.
ER -