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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-\n                      <jats:italic toggle=\"yes\">M.tb<\/jats:italic>\n                      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.,\n                      <jats:italic toggle=\"yes\">Runx2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Runx3<\/jats:italic>\n                      in T cells;\n                      <jats:italic toggle=\"yes\">Tcf4<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Pou2f2<\/jats:italic>\n                      in B cells) and upregulation of regulators driving regulatory or suppressive phenotypes (e.g.,\n                      <jats:italic toggle=\"yes\">Ikzf2<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">tuberculosis<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        While 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\n                        <jats:italic toggle=\"yes\">M.tb<\/jats:italic>\n                        . 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.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01199-26","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:01:13Z","timestamp":1784898073000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell transcriptomics reveal PD-1-loss-driven immune dysregulation of pulmonary lymphocytes during early\n                    <i>Mycobacterium tuberculosis<\/i>\n                    infection"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1183-3708","authenticated-orcid":true,"given":"Bing","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003hwx626","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University","place":["Wuhan, China"]},{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Veterinary Medicine, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoqi","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003hwx626","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University","place":["Wuhan, China"]},{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Veterinary Medicine, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003hwx626","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University","place":["Wuhan, China"]},{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Life Sciences and Technology, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinru","family":"Cai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Veterinary Medicine, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Cao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Chinese Academy of Sciences","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3790-8912","authenticated-orcid":true,"given":"Xuan","family":"Ma","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04j7b2v61","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Agriculture, Ningxia University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7060-5185","authenticated-orcid":true,"given":"Jinxia","family":"Dai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/003hwx626","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University","place":["Wuhan, China"]},{"id":[{"id":"https:\/\/ror.org\/023b72294","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Veterinary Medicine, Huazhong Agricultural University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"WHO. 2025. 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