{"doi":"10.1172/jci.insight.142680","title":"Exhausted-like CD8+ T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects","abstract":"Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic β cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent-onset T1D, endogenous insulin production was preserved in 30% of subjects for 2 years after therapy. Given our previous findings linking exhausted-like CD8+ T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8+ T cells to evaluate their potential role in T1DAL. Using RNA sequencing, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into 2 CD8 memory phenotypes through correlation with cytometry data. These cells were hypoproliferative, shared expanded rearranged TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The 2 phenotypes could be distinguished by reciprocal expression of CD8+ T and NK cell markers (GZMB, CD57, and inhibitory killer cell immunoglobulin-like receptor [iKIR] genes), versus T cell activation and differentiation markers (PD-1 and CD28). These findings support previous evidence linking exhausted-like CD8+ T cells to successful immune interventions for T1D, while suggesting that multiple inhibitory mechanisms can promote this beneficial cell state.","journal":"JCI Insight","year":2020,"id":58763,"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":71,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":272838,"name":"Elisavet Serti","orcid":null,"position":1,"is_corresponding":false},{"id":308286,"name":"Virginia Muir","orcid":"0000-0002-6384-4572","position":2,"is_corresponding":false},{"id":309404,"name":"Mario G. Rosasco","orcid":null,"position":3,"is_corresponding":false},{"id":308287,"name":"Tingting Lü","orcid":"0000-0003-1339-9877","position":4,"is_corresponding":false},{"id":308288,"name":"Elisa Balmas","orcid":"0000-0002-4600-6809","position":5,"is_corresponding":false},{"id":271015,"name":"Gerald T. Nepom","orcid":"0000-0002-8063-1464","position":6,"is_corresponding":false},{"id":308289,"name":"S. Alice Long","orcid":"0000-0002-0281-1240","position":7,"is_corresponding":false},{"id":308290,"name":"Peter S. Linsley","orcid":"0000-0002-8960-4307","position":8,"is_corresponding":false},{"id":308285,"name":"Kirsten E. Diggins","orcid":"0000-0003-1622-0158","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T21:07:33.416320Z","pmid":"33351781","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":[]}