Exhausted-like CD8+ T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects

• Published in: JCI insight Vol. 6; no. 3
• Main Authors: Diggins, Kirsten E., Serti, Elisavet, Muir, Virginia, Rosasco, Mario, Lu, TingTing, Balmas, Elisa, Nepom, Gerald, Long, S. Alice, Linsley, Peter S.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.02.2021; American Society for Clinical investigation
• Subjects: Adolescent; Adult; Alefacept - therapeutic use; Autoimmunity; C-Peptide - biosynthesis; C-Peptide - genetics; CD57 Antigens - metabolism; CD8-Positive T-Lymphocytes - classification; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Child; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - therapy; Double-Blind Method; Female; Humans; Immunologic Factors - therapeutic use; Immunologic Memory - genetics; Immunology; Immunophenotyping; Killer Cells, Natural - immunology; Lectins, C-Type - metabolism; Lymphocyte Activation; Male; Programmed Cell Death 1 Receptor - metabolism; Receptors, Immunologic - metabolism; RNA-Seq; Young Adult; Autoimmunity; Adaptive immunity; Immunology; Autoimmune diseases; T cells
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.142680

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.