Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes

Cell Immunol. 2017 Sep;319:3-9. doi: 10.1016/j.cellimm.2017.07.007. Epub 2017 Aug 18.

Abstract

The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.

Keywords: Anti-CD3 monoclonal antibody; Immune tolerance; Immunotherapy; T cell inactivation; T lymphocyte; Type 1 diabetes.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • C-Peptide / agonists
  • C-Peptide / genetics
  • C-Peptide / immunology
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • CD57 Antigens / genetics
  • CD57 Antigens / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Child
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Immune Tolerance / drug effects*
  • Immunomodulation
  • Immunotherapy / methods
  • Interleukin-7 Receptor alpha Subunit / genetics
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Male
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Trans-Activators / genetics
  • Trans-Activators / immunology

Substances

  • Antibodies, Monoclonal, Humanized
  • C-Peptide
  • CD3 Complex
  • CD57 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Hypoglycemic Agents
  • Interleukin-7 Receptor alpha Subunit
  • KLRG1 protein, human
  • Lectins, C-Type
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TIGIT protein, human
  • Trans-Activators
  • teplizumab