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To investigate tissue-specific immune responses to CMV, we analysed paired peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMNCs) from HCMV-seropositive donors using multiparametric flow cytometry and cytokine FluroSpot assays. We assessed immune cell composition, memory T cell subsets, cytokine production, cytotoxic potential, activation marker expression, and checkpoint inhibitory receptor (CIR) profiles, both ex vivo and following stimulation with lytic and latent HCMV antigens. BMMNCs were enriched in CD34+ progenitor cells and exhibited distinct T cell memory subset distributions. HCMV-specific responses were compartmentalised: IFN-\u03b3 responses predominated in PBMCs following lytic antigen stimulation, while IL-10 and TNF-\u03b1 responses were more prominent in BMMNCs, particularly in response to latent antigens. US28-specific T cells in the BM showed elevated expression of CD39, PD-1, BTLA, CTLA-4, ICOS, and LAG-3 on CD4+ T cells and increased expression of PD-1, CD39, BTLA, TIGIT, LAG-3, and ICOS on CD8+ T cell populations, suggesting a more immunoregulatory phenotype. These findings highlight functional and phenotypic differences in HCMV-specific T cell responses between blood and bone marrow, underscoring the role of the BM niche in shaping antiviral immunity and maintaining viral latency.<\/jats:p>","DOI":"10.3390\/pathogens14080722","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:45:18Z","timestamp":1753173918000},"page":"722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Distinct Immunological Landscapes of HCMV-Specific T Cells in Bone Marrow and Peripheral Blood"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4230-9220","authenticated-orcid":false,"given":"Sarah E.","family":"Jackson","sequence":"first","affiliation":[{"name":"Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Cambridge Biomedical Campus, School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6190-5895","authenticated-orcid":false,"given":"Rosie","family":"Fairclough","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Cambridge Biomedical Campus, School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Romashova","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Cambridge Biomedical Campus, School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Okecha","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Cambridge Biomedical Campus, School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Wills","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Cambridge Biomedical Campus, School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.4049\/jimmunol.1800171","article-title":"Cytomegalovirus: Shape-Shifting the Immune System","volume":"200","author":"Picarda","year":"2018","journal-title":"J. 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