{"doi":"10.1093/jimmun/vkae014","title":"Early expansion of TIGIT+PD1+ effector memory CD4 T cells via agonistic effect of alefacept in new-onset type 1 diabetes","abstract":"The CD2-depleting drug alefacept (LFA3-Ig) preserved beta cell function in new-onset type 1 diabetes (T1D) patients. The most promising biomarkers of response were late expansion of exhausted CD8 T cells and rare baseline inflammatory islet-reactive CD4 T cells, neither of which can be used to measure responses to drug in the weeks after treatment. Thus, we investigated whether early changes in T cell immunophenotypes could serve as biomarkers of drug activity. We characterized T cell responses by flow cytometry and identified an exhausted-like population of CD2low CD4 effector memory T cells coexpressing TIGIT and PD1 that expanded by 11 wk after the start of treatment. This population was not entirely spared from alefacept-mediated depletion in vivo or in vitro but recovered through homeostatic proliferation of CD2low cells in vivo. Proliferation of TIGIT+PD1+ effector memory CD4 T cells increased with treatment, with a concomitant reduction of proinflammatory cytokine production. The persistent increase of TIGIT+PD1+ effector memory CD4 T cells was specific to alefacept treatment; 2 other T cell depleting therapies, teplizumab and anti-thymocyte globulin, induced only a transient increase in this CD4 population. Our data suggest that the expanding TIGIT+PD1+ effector memory CD4 T cell population represents a promising biomarker of early treatment effects of alefacept. The nondepleting effects on proliferation and cytokine production also suggest agonistic activity by this CD2 targeted therapy.","journal":"The Journal of Immunology","year":2025,"id":531895,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"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":927813,"name":"Laura A. Cooney","orcid":"0000-0001-7307-2548","position":1,"is_corresponding":false},{"id":1173367,"name":"Elisavet Serti","orcid":"0000-0003-4129-0254","position":2,"is_corresponding":false},{"id":1412679,"name":"Duangchan Suwannasaen","orcid":"0000-0003-4000-7592","position":3,"is_corresponding":false},{"id":308286,"name":"Virginia Muir","orcid":"0000-0002-6384-4572","position":4,"is_corresponding":false},{"id":328022,"name":"Alice Wiedeman","orcid":"0000-0001-7329-7288","position":5,"is_corresponding":false},{"id":256536,"name":"Kristina M. Harris","orcid":"0000-0002-6957-514X","position":6,"is_corresponding":false},{"id":1290878,"name":"Jorge Pardo","orcid":"0009-0005-7657-4099","position":7,"is_corresponding":false},{"id":235418,"name":"Mark S. Anderson","orcid":"0000-0002-3093-4758","position":8,"is_corresponding":false},{"id":271012,"name":"Cate Speake","orcid":"0000-0003-1480-4272","position":9,"is_corresponding":false},{"id":271015,"name":"Gerald T. Nepom","orcid":"0000-0002-8063-1464","position":10,"is_corresponding":false},{"id":308290,"name":"Peter S. Linsley","orcid":"0000-0002-8960-4307","position":11,"is_corresponding":false},{"id":333914,"name":"Srinath Sanda","orcid":"0000-0002-6983-6864","position":12,"is_corresponding":false},{"id":308289,"name":"S. Alice Long","orcid":"0000-0002-0281-1240","position":13,"is_corresponding":false},{"id":675695,"name":"Lauren E. Higdon","orcid":"0000-0002-6470-6155","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:51:18.928280Z","pmid":"40073269","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":[]}