{"doi":"10.1172/jci.insight.159205","title":"Linked sensitization by memory CD4+ T cells prevents costimulation blockade–induced transplantation tolerance","abstract":"Dominant infectious tolerance explains how brief tolerance-inducing therapies result in lifelong tolerance to donor antigens and \"linked\" third-party antigens, while recipient sensitization and ensuing immunological memory prevent the successful induction of transplant tolerance. In this study, we juxtapose these 2 concepts to test whether mechanisms of dominant infectious tolerance can control a limited repertoire of memory T and B cells. We show that sensitization to a single donor antigen is sufficient to prevent stable transplant tolerance, rendering it unstable. Mechanistic studies revealed that recall antibody responses and memory CD8+ T cell expansion were initially controlled, but memory CD4+Foxp3- T cell (Tconv) responses were not. Remarkably, naive donor-specific Tconvs at tolerance induction also acquired a resistance to tolerance, proliferating and acquiring a phenotype similar to memory Tconvs. This phenomenon of \"linked sensitization\" underscores the challenges of reprogramming a primed immune response toward tolerance and identifies a potential therapeutic checkpoint for synergizing with costimulation blockade to achieve transplant tolerance in the clinic.","journal":"JCI Insight","year":2022,"id":278637,"datarank":0.31400329591834597,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.022116773560048902,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.022116773560048902,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"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":394624,"name":"James S. Young","orcid":"0000-0003-2209-2690","position":1,"is_corresponding":false},{"id":681695,"name":"Jared M. Pollard","orcid":"0000-0003-1921-1708","position":2,"is_corresponding":false},{"id":396109,"name":"Dengping Yin","orcid":null,"position":3,"is_corresponding":false},{"id":92114,"name":"Maria‐Luisa Alegre","orcid":"0000-0001-5707-6194","position":4,"is_corresponding":false},{"id":72297,"name":"Anita S. Chong","orcid":"0000-0003-0460-0196","position":5,"is_corresponding":false},{"id":456819,"name":"Michael S. Andrade","orcid":"0000-0002-1404-3015","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:28:47.357993Z","pmid":"35674134","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":[]}