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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Human immunodeficiency virus (HIV) and\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      (Mtb) co-infection remains a major cause of mortality in AIDS patients, yet the mechanisms of pathogen interplay and host immune remodeling remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To capture early untreated states, we applied single-cell RNA sequencing (scRNA-seq) to peripheral blood mononuclear cells from healthy controls, and from participants newly diagnosed with HIV mono-infection or HIV-Mtb co-infection, before therapy initiation. Integration guided by a Directed Acyclic Graph (DAG) inferred a pseudo-temporal trajectory from health to HIV infection to co-infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Along this continuum, TNF-\u03b1 and TGF-\u03b2 signaling progressively declined in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and monocytes. Th1 cells emerged as the dominant anti-\n                      <jats:italic>tuberculosis<\/jats:italic>\n                      effectors, whereas Th17 cells exhibited transcriptional exhaustion and ribosomal stress signatures consistent with a non-responsive state. Cell communication analysis revealed fewer overall interactions but increased signaling strength within pathways during co-infection. Notably, we observed a transition in T cell from MHC class II to class I, a shift that was most pronounced in the CD4\n                      <jats:sup>+<\/jats:sup>\n                      effector memory subset. These rewired interactions featured selective upregulation of inhibitory checkpoint molecules (PGE2\u2013PTGES3\u2013PTGER2\/4, PPIA-BSG, PECAM1) and loss of stimulatory signals (CD6-ALCAM, CLEC2B\/C\/D-KLRB1).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study provides a single-cell roadmap of HIV-Mtb co-infection and identifies Th1\/Th17 imbalance and MHC-I-biased T-cell signaling reconfiguration as candidate targets for restoring immune homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1680538","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:28:17Z","timestamp":1764311297000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Single\u2010cell transcriptomics reveals pathogen interactions and T cell 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