Co-stimulatory and Co-inhibitory Pathways in Autoimmunity

Immunity. 2016 May 17;44(5):1034-51. doi: 10.1016/j.immuni.2016.04.017.


The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. Although co-stimulation is essential for boosting and shaping the initial response following signaling through the antigen receptor, inhibitory pathways are also critical for modulating the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance and thus to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (systemic lupus erythematosus and rheumatoid arthritis) and two organ-specific (multiple sclerosis and type 1 diabetes) emblematic autoimmune diseases. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / therapy
  • Autoimmunity
  • Costimulatory and Inhibitory T-Cell Receptors / metabolism*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / therapy
  • Humans
  • Immunotherapy / methods*
  • Immunotherapy / trends
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / therapy
  • Lymphocyte Activation
  • Molecular Targeted Therapy
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / therapy
  • Receptor Cross-Talk*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology*


  • Costimulatory and Inhibitory T-Cell Receptors
  • Receptors, Antigen, T-Cell