{"doi":"10.1101/2025.08.01.668160","title":"Hemoglobin alpha regulates T-lymphocyte activation and mitochondrial function","abstract":"Abstract We have recently discovered hemoglobin alpha a1 (Hbα-a1 mRNA and Hbα protein) in T-lymphocytes and previously reported that its expression was sensitive to mitochondrial redox perturbations. However, outside of its occurrence and basic characterization, the functional role of Hbα in T-lymphocytes remained unknown. Herein, we identify Hbα in both CD4 + and CD8 + T-lymphocyte subsets, and found its expression is highly dynamic, differs between the two subtypes, and is dependent upon activation stage. Further, the loss of Hbα by use of a novel T-lymphocyte-specific Hbα knock-out mouse impairs mitochondrial function, dysregulates cytokine production, and lowers the activation threshold primarily in CD4 + T-lymphocytes, indicating a critical role for Hbα within this subset. While these data suggested the loss of Hbα in T-lymphocytes may promote aberrant activation of autoreactive T-lymphocytes, surprisingly, we discovered that mice lacking Hbα in T-lymphocytes exhibited reduced severity of experimental autoimmune encephalomyelitis (EAE) compared to wild-type control animals. Interestingly, T-lymphocytes lacking Hbα in vivo appeared to function identically to wild-type controls, which did not explain the protection against EAE. In contrast, T-lymphocyte Hbα knock-out mice displayed significantly reduced levels of circulating immunoglobulins and CD40L expression compared to their wild-type counterparts during EAE, suggesting possible impaired intercellular communication. These data elucidate a previously unrecognized role for Hbα in T-lymphocyte function, which may have implications for hemoglobin-related diseases (i.e., hemoglobinopathies).","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571557,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":923286,"name":"Tatlock H. Lauten","orcid":null,"position":1,"is_corresponding":false},{"id":1221472,"name":"Tamara Natour","orcid":"0009-0005-1084-464X","position":2,"is_corresponding":false},{"id":1281944,"name":"Lauren Pitts","orcid":null,"position":3,"is_corresponding":false},{"id":1233797,"name":"Caroline N Jojo","orcid":null,"position":4,"is_corresponding":false},{"id":1416922,"name":"Brooke Griffin","orcid":"0000-0003-2870-7350","position":5,"is_corresponding":false},{"id":1477675,"name":"Sreeram Pasupuleti","orcid":null,"position":6,"is_corresponding":false},{"id":314765,"name":"Adam J. Case","orcid":"0000-0003-3404-1428","position":7,"is_corresponding":false},{"id":1258927,"name":"Emily Reed","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:57:15.755535Z","pmid":"40766506","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":[]}