Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes

• DOI: 10.1172/jci.insight.167881
• Publication Date: 2023-09-26T16:00:54Z
• Authors: Elisa Balmas; Janice Chen; Alex K. Hu; Hannah A. DeBerg; Mario G. Rosasco; Vivian H. Gersuk; Elisavet Serti; Cate Speake; Carla J. Greenbaum; Gerald T. Nepom; Peter S. Linsley; Karen Cerosaletti
• Keywords: Proinflammatory cytokine

Variation in the preservation of β cell function clinical trials type 1 diabetes (T1D) has emphasized need to define biomarkers predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3-Ig) and demonstrated C-peptide approximately 30% new-onset T1D individuals. We analyzed islet antigen-reactive (IAR) CD4+ PBMC samples collected prior from alefacept- placebo-treated individuals using flow cytometry single-cell RNA sequencing. IAR at baseline had heterogeneous phenotypes. Transcript profiles formed phenotypic clusters along a trajectory based on increasing maturation activation, receptor (TCR) chains showed clonal expansion. Notably, frequency memory phenotype unique transcript profile (cluster 3) were inversely correlated alefacept-treated, but not placebo-treated, Cluster 3 proinflammatory characterized by expression transcription factor BHLHE40 cytokines GM-CSF TNF-α, shared TCR effector memory-like clusters. Our results suggest as potential biomarker response therapies targeting CD2 pathway warrant investigation for other cell-related therapies.