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Single-cell transcriptomics reveal PD-1-loss-driven immune dysregulation of pulmonary lymphocytes during early Mycobacterium tuberculosis infection.

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Τίτλος: Single-cell transcriptomics reveal PD-1-loss-driven immune dysregulation of pulmonary lymphocytes during early Mycobacterium tuberculosis infection.
Συγγραφείς: Yang B; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China., Wang H; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China., Zhang S; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.; College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, China., Cai J; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China., Cao G; Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China., Ma X; College of Agriculture, Ningxia University, Yinchuan, China., Dai J; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Πηγή: Microbiology spectrum [Microbiol Spectr] 2026 Sep; Vol. 14 (9), pp. e0119926. Date of Electronic Publication: 2026 Jul 24.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: ASM Press Country of Publication: United States NLM ID: 101634614 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2165-0497 (Electronic) Linking ISSN: 21650497 NLM ISO Abbreviation: Microbiol Spectr Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, DC : ASM Press, 2013-
Ιατρικοί όροι (MeSH): Programmed Cell Death 1 Receptor*/genetics , Programmed Cell Death 1 Receptor*/immunology , Programmed Cell Death 1 Receptor*/deficiency , Mycobacterium tuberculosis*/immunology , Mycobacterium tuberculosis*/genetics , Lung*/immunology , Lung*/microbiology , Tuberculosis*/immunology , Tuberculosis*/genetics , Tuberculosis*/microbiology , Lymphocytes*/immunology, B-Lymphocytes/immunology ; T-Lymphocytes, Regulatory/immunology ; Animals ; Mice ; Mice, Inbred C57BL ; Single-Cell Analysis ; Mice, Knockout ; Transcriptome ; T-Cell Exhaustion
Περίληψη: Although PD-1 blockade shows strong antitumor efficacy and is being considered for chronic infections including Mycobacterium tuberculosis (M.tb), its influence on early lymphocyte responses to M.tb remains poorly understood. In this study, we characterized the transcriptional and developmental states of pulmonary B and T cells in mice lacking PD-1 after 7 days post-M.tb infection. We found that loss of PD-1 disturbed pulmonary lymphocyte homeostasis, characterized by abnormal regulatory T cell (Tregs) expansion, early exhaustion-like differentiation of cytotoxic T cells, and impaired maturation of memory B cells. These alterations are associated with changes in key transcriptional regulators, including reduced activity of factors promoting effector differentiation (e.g., Runx2, Runx3 in T cells; Tcf4, Pou2f2 in B cells) and upregulation of regulators driving regulatory or suppressive phenotypes (e.g., Ikzf2 in Tregs). Additionally, PD-1 deficiency rewired B-T cell communication with diminished antigen presentation and co-stimulation while amplifying proinflammatory signals. These insights provide a transcriptional blueprint for PD-1-mediated immune balance, with implications for host-directed therapies in tuberculosis.IMPORTANCEWhile PD-1 inhibition can boost protective T cell responses, it has also been linked to increased TB susceptibility. Our study reveals that PD-1 plays a previously unrecognized role in shaping the earliest immune responses to M.tb. In mice lacking PD-1, lung lymphocytes failed to develop in a balanced manner: regulatory T cells expanded excessively, cytotoxic T cells showed signs of early exhaustion, and memory B cell maturation was delayed. These changes disrupted the normal communication between B and T cells, weakening adaptive immunity while amplifying inflammation. By defining PD-1 as a critical organizer of early lymphocyte fate, our findings highlight the risks of indiscriminate PD-1 blockade in infectious contexts and point toward more precise strategies for host-directed TB therapies and vaccine design.
Competing Interests: The authors declare no conflict of interest.
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Grant Information: 82272416, U21A20259 National Natural Science Foundation of China
Contributed Indexing: Keywords: Mycobacterium tuberculosis; cellular communication; programmed cell death receptor 1; pulmonary lymphocytes; transcriptional regulatory networks; transcriptomic landscape
Molecular Sequence: GEO GSE261737
Substance Nomenclature: 0 (Programmed Cell Death 1 Receptor)
0 (Pdcd1 protein, mouse)
Entry Date(s): Date Created: 20260724 Date Completed: 20260902 Latest Revision: 20260911
Update Code: 20260912
PubMed Central ID: PMC13532292
DOI: 10.1128/spectrum.01199-26
PMID: 42496156
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2165-0497
DOI:10.1128/spectrum.01199-26