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

JCI Insight. 2021 Feb 8;6(3):e142680. 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.

Keywords: Adaptive immunity; Autoimmune diseases; Autoimmunity; Immunology; T cells.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Alefacept / therapeutic use*
  • 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
  • Immunophenotyping
  • Killer Cells, Natural / immunology
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation
  • Male
  • Programmed Cell Death 1 Receptor / metabolism
  • RNA-Seq
  • Receptors, Immunologic / metabolism
  • Young Adult


  • C-Peptide
  • CD57 Antigens
  • Immunologic Factors
  • KLRG1 protein, human
  • Lectins, C-Type
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TIGIT protein, human
  • Alefacept