Human memory CD4 + T cells recognize non-infected macrophage bystanders exposed to Mycobacterium tuberculosis -infected cells
Year: 2026
Type: preprint
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.
Institutions: University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Case Western Reserve University, Portland VA Medical Center, Oregon Health & Science University, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology, University of Massachusetts Chan Medical School
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2465350294, G360764017, G5292295948, G5965130064, Overcoming restrained lung trafficking by memory CD4+ T cells to prevent active tuberculosis in people living with HIV, G7180211660, G7578466963, G8669742766, Determining Protective Features of Human Memory T-cells to Inform Mycobacterium tuberculosis Vaccine Development, Evaluating human T cells specific for Mycobacterium tuberculosis antigens that are processed and presented by infected macrophages
OpenAlex ID: W7214349667