{"doi":"10.1101/2024.11.27.625710","title":"Polyfunctional IL-21 <sup>+</sup> IFNγ <sup>+</sup> T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy","abstract":"ABSTRACT Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8 + T cells, the role for CD4 + T cells in ICI-T1DM is less understood. Here, we identify expansion CD4 + T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNγ) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNγ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNγ both signal through JAK-STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4 + Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE. VISUAL ABSTRACT","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":492522,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"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":998555,"name":"Jessica Ortega","orcid":"0009-0006-4460-8896","position":1,"is_corresponding":false},{"id":1339252,"name":"Kyleigh Kimbrell","orcid":null,"position":2,"is_corresponding":false},{"id":1339253,"name":"Joah Lee","orcid":null,"position":3,"is_corresponding":false},{"id":998440,"name":"Lauren N Scott","orcid":"0009-0006-3377-8734","position":4,"is_corresponding":false},{"id":1339254,"name":"Esther Peluso","orcid":null,"position":5,"is_corresponding":false},{"id":792861,"name":"Sarah Wang","orcid":"0000-0001-8819-6447","position":6,"is_corresponding":false},{"id":1339255,"name":"Ellie Kao","orcid":null,"position":7,"is_corresponding":false},{"id":855987,"name":"Kristy Kim","orcid":"0000-0002-3869-4939","position":8,"is_corresponding":false},{"id":681167,"name":"Jarod Olay","orcid":null,"position":9,"is_corresponding":false},{"id":308642,"name":"Zoe Quandt","orcid":"0000-0002-4568-4368","position":10,"is_corresponding":false},{"id":748459,"name":"Trevor E. Angell","orcid":"0000-0002-9929-0188","position":11,"is_corresponding":false},{"id":339087,"name":"Maureen A. Su","orcid":"0000-0002-3680-9982","position":12,"is_corresponding":false},{"id":748461,"name":"Melissa G. Lechner","orcid":"0000-0002-4744-6566","position":13,"is_corresponding":false},{"id":998554,"name":"Nicole Huang","orcid":"0009-0001-8426-3451","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:08:56.210382Z","pmid":"39677814","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":[]}