Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy

Research output: Contribution to journalReview article

71 Scopus citations

Abstract

Pro-inflammatory CD4+ T-cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen-presenting cells presenting self antigen to self-reactive interferon-γ and interleukin-17-producing CD4+ T-helper (Th) type 1/Th17 cells. To date, the majority of Food and Drug Administration-approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments, which allow for the directed blockade of the deleterious effects of self-reactive immune cell function. According to the two-signal hypothesis, activation of a naive antigen-specific CD4+ T cell requires both stimulation of the T-cell receptor (TCR) (signal 1) and stimulation of costimulatory molecules (signal 2). There also exists a balance between pro-inflammatory and anti-inflammatory immune cell activity, which is regulated by the type and strength of the activating signal as well as the local cytokine milieu in which the naive CD4+ T cell is activated. To this end, the majority of ongoing research is focused on the delivery of suboptimal TCR stimulation in the absence of costimulatory molecule stimulation, or potential blockade of stimulatory accessory molecules. Therefore, the signaling pathways involved in the induction of CD4+ T-cell anergy, as apposed to activation, are topics of intense interest.

Original languageEnglish (US)
Pages (from-to)337-355
Number of pages19
JournalImmunological Reviews
Volume229
Issue number1
DOIs
StatePublished - May 1 2009

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Keywords

  • Antigens/peptides/epitopes
  • Cell activation
  • Cell surface molecules
  • Experimental autoimmune encephalitis/multiple sclerosis
  • T cells
  • Th1/Th2/Th17cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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