{"doi":"10.1101/2024.01.10.574913","title":"Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants","abstract":"Abstract Several coinhibitory receptors are upregulated upon activation, whereas a small number of coinhibitory receptors are expressed constitutively by naive T cells. The relationship between constitutively expressed coinhibitors is unknown. We found an inverse relationship between two constitutively expressed coinhibitors, CD5 and BTLA; BTLA expression was low in the thymus and high in the periphery, corresponding respectively with high and low CD5 expression. Germline or induced deletion of Btla in somatic cells demonstrated a causal relationship between BTLA expression and CD5 levels in T cells of central and peripheral lymphoid tissues. The effect of BTLA on CD5 expression on thymic and peripheral CD4 T cells was due to BTLA signaling, rather than signaling by its ligand, the herpes virus mediator (HVEM). Regulation was maintained in mice with a non-signaling HVEM mutant but was lost in Tnfrsf14 −/− ( Hvem −/− ) mice. Increased CD5 levels have been positively associated with increased recognition of self-peptide MHC complexes. Thus, control of CD5 expression by BTLA signals early in T cell ontogeny suggested that BTLA might be important for establishing self-tolerance in newly generated T cells. Consistent with this concept, we found that BTLA, as well as the inducible coinhibitor PD-1, were needed post thymic selection in recent thymic emigrants (RTE) to establish self-tolerance. RTE lacking BTLA caused a multiorgan autoimmune disease whose development required CD4 T cells and MHC class II. Together, our findings identify a negative regulatory pathway allowing constitutively expressed coinhibitory receptors to calibrate their expression in thymic T cell differentiation. Expression of constitutive and induced coinhibitory receptors is needed to establish tolerance in the periphery for RTE.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489644,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":597280,"name":"Govindarajan Thangavelu","orcid":"0000-0003-3524-9570","position":1,"is_corresponding":false},{"id":700694,"name":"Ting-Fang Chou","orcid":"0000-0001-7095-3518","position":2,"is_corresponding":false},{"id":1303297,"name":"Marcos Petersen","orcid":"0000-0003-2093-7194","position":3,"is_corresponding":false},{"id":700696,"name":"Kiyokazu Kakugawa","orcid":"0000-0002-2560-5562","position":4,"is_corresponding":false},{"id":1303298,"name":"Julia F. May","orcid":"0000-0003-3948-3444","position":5,"is_corresponding":false},{"id":1303299,"name":"Kevin Joannou","orcid":"0009-0000-2764-2028","position":6,"is_corresponding":false},{"id":584531,"name":"Qingyang Wang","orcid":"0000-0002-9999-3019","position":7,"is_corresponding":false},{"id":1303300,"name":"Kristofor K. Ellestad","orcid":"0000-0001-9350-4977","position":8,"is_corresponding":false},{"id":473147,"name":"Louis Boon","orcid":"0000-0002-0937-9171","position":9,"is_corresponding":false},{"id":1303301,"name":"Peter A. Bretscher","orcid":"0000-0002-9156-9846","position":10,"is_corresponding":false},{"id":584535,"name":"Hilde Cheroutre","orcid":"0000-0002-3669-2964","position":11,"is_corresponding":false},{"id":266586,"name":"Mitchell Kronenberg","orcid":"0000-0001-6318-6445","position":12,"is_corresponding":false},{"id":1303302,"name":"Troy A. Baldwin","orcid":"0000-0002-0122-3746","position":13,"is_corresponding":false},{"id":484745,"name":"Colin C. Anderson","orcid":"0000-0001-7815-2416","position":14,"is_corresponding":false},{"id":1303296,"name":"Adeolu Adegoke","orcid":"0000-0003-0886-9678","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:28.548530Z","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":[]}