{"doi":"10.1128/jvi.00746-23","title":"Functional and transcriptional heterogeneity within the massively expanding HLADR <sup>+</sup> CD38 <sup>+</sup> CD8 T cell population in acute febrile dengue patients","abstract":"ABSTRACT CD8 T cells are important tools for protection against intracellularly replicating pathogens such as viruses. Previous studies showed that a discrete population of HLADR and CD38-expressing CD8 T cells expands massively during the acute febrile phase of human dengue virus infection—but very few of these cells secrete IFNγ upon in vitro stimulation with dengue peptides. To gain a better understanding of what other cytokines/chemokines do these massively expanding HLADR + CD38 + CD8 T cells express, we performed RNA seq of sorted HLADR + CD38 + CD8 T cell subsets after peptide stimulation. A majority of these peptide-stimulated HLADR + CD38 + CD8 T cells were CD69 - IFNγ - , nearly a third were CD69 + IFNγ - , whereas very few (&lt;10%) were CD69 + IFNγ + . The CD69 - IFNγ - subset was enriched for the expression of key genes implicated in the negative regulation of T cell receptor (TCR) signaling and T-cell exhaustion, attraction of B cells and other lymphocytes, and cytokines related to Tc17/T-reg lineages or those that are implicated in immunosuppression/immunomodulatory and anti-inflammatory activities and angiogenesis. The CD69 + IFNγ - subset showed enriched transcription of key genes implicated in cytotoxic effector functions as well as costimulatory and signaling adaptors implicated in fine balancing of T cell receptor signaling. The CD69 + IFNγ + subset largely shared the transcriptional profile with the CD69 + IFNγ - subset—but with relatively more pronounced expression along with additional genes such as chemokines XCL1/XCL2. Our findings showing distinct functional subsets among these massively expanding CD8 T cells in dengue CD8 T cells warrant further studies to carefully examine the precise role of these T cell subsets in protection against dengue. IMPORTANCE CD8 T cells play a crucial role in protecting against intracellular pathogens such as viruses by eliminating infected cells and releasing anti-viral cytokines such as interferon gamma (IFNγ). Consequently, there is significant interest in comprehensively characterizing CD8 T cell responses in acute dengue febrile patients. Previous studies, including our own, have demonstrated that a discrete population of CD8 T cells with HLADR + CD38 + phenotype undergoes massive expansion during the acute febrile phase of natural dengue virus infection. Although about a third of these massively expanding HLADR + CD38 + CD8 T cells were also CD69 high when examined ex vivo , only a small fraction of them produced IFNγ upon in vitro peptide stimulation. Therefore, to better understand such functional diversity of CD8 T cells responding to dengue virus infection, it is important to know the cytokines/chemokines expressed by these peptide-stimulated HLADR + CD38 + CD8 T cells and the transcriptional profiles that distinguish the CD69 + IFNγ + , CD69 + IFNγ - , and CD69 - IFNγ - subsets.","journal":"Journal of Virology","year":2023,"id":385491,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9469,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":879805,"name":"Prashant Bajpai","orcid":"0000-0002-8443-9787","position":1,"is_corresponding":false},{"id":373037,"name":"Deepti Maheshwari","orcid":null,"position":2,"is_corresponding":false},{"id":372012,"name":"Yadya M. 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Aggarwal","orcid":"0000-0002-3937-7839","position":9,"is_corresponding":false},{"id":423967,"name":"Shweta Jain","orcid":"0000-0001-6297-0078","position":10,"is_corresponding":false},{"id":1153940,"name":"Chaitanya Verma","orcid":null,"position":11,"is_corresponding":false},{"id":1007529,"name":"Priyanka Singla","orcid":"0000-0002-5349-3123","position":12,"is_corresponding":false},{"id":1007530,"name":"Manish Soneja","orcid":"0000-0002-8619-7929","position":13,"is_corresponding":false},{"id":1007531,"name":"Naveet Wig","orcid":"0000-0002-6603-601X","position":14,"is_corresponding":false},{"id":372020,"name":"Kaja Murali‐Krishna","orcid":"0000-0002-6275-1710","position":15,"is_corresponding":false},{"id":372018,"name":"Anmol Chandele","orcid":"0000-0002-5702-7170","position":16,"is_corresponding":false},{"id":372015,"name":"Prabhat Singh","orcid":"0009-0004-6952-992X","position":0,"is_corresponding":true}],"reference_count":106,"raw_metadata":null,"created_at":"2026-07-19T01:17:52.636565Z","pmid":"37855600","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}