{"doi":"10.1101/2022.01.26.477910","title":"T-lymphocyte Tyrosine Hydroxylase Regulates T <sub>H</sub> 17 T-lymphocytes during Repeated Social Defeat Stress","abstract":"Abstract Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which results in deleterious changes to psychological and physical health. Patients with PTSD are especially susceptible to co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (T H 17) lymphocyte-driven inflammation. While the exact mechanism of this increased inflammation is unknown, overactivity of the sympathetic nervous system is a hallmark of PTSD. Neurotransmitters of the sympathetic nervous system (i.e., catecholamines) can alter T-lymphocyte function, which we have previously demonstrated to be partially mitochondrial redox-mediated. Furthermore, we have previously elucidated that T-lymphocytes generate their own catecholamines, and strong associations exist between tyrosine hydroxylase (TH; the rate-limiting enzyme in the synthesis of catecholamines) and pro-inflammatory interleukin 17A (IL-17A) expression within purified T-lymphocytes in a preclinical rodent model of PTSD. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive T H 17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (TH T-KO ) were subjected to repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor-α (TNFα), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (T H 17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of TH T-KO animals. When activated ex vivo, secretion of IL-17A and IL-22 by TH T-KO T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, TH T-KO T-lymphocytes were still able to polarize to T H 17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed TH T-KO T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and T H 17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced T H 17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":307046,"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":0.9627,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":484313,"name":"Cassandra M. Moshfegh","orcid":"0000-0002-5608-1976","position":1,"is_corresponding":false},{"id":314766,"name":"Gabrielle F. Watson","orcid":"0000-0002-5510-227X","position":2,"is_corresponding":false},{"id":314765,"name":"Adam J. Case","orcid":"0000-0003-3404-1428","position":3,"is_corresponding":false},{"id":484312,"name":"Safwan Elkhatib","orcid":"0000-0003-3946-8658","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T00:32:52.703737Z","pmid":null,"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":[]}