CD4+CD28- costimulation-independent T cells in multiple sclerosis

J Clin Invest. 2001 Oct;108(8):1185-94. doi: 10.1172/JCI12516.


Multiple lines of evidence suggest that CD4+ lymphocytes initiate autoimmune responses against myelin antigens in multiple sclerosis (MS). The increased frequency of activated myelin-specific cells in MS patients indicates that the activation of autoreactive cells represents a central event in the pathogenesis of the disease. We identified a CD4+ subpopulation that is characterized phenotypically by the persistent absence of surface CD28 expression and functionally by CD28-independent activation and Th1 cytokine secretion. Owing to their costimulation-independent activation and their expression of a full agonist signaling activation pattern, CD4+CD28- cells have the potential to initiate autoimmune responses in the central nervous system, a compartment devoid of professional antigen presenting cells. Long-term memory CD4+CD28- cells produce high amounts of IFN-gamma and maximally upregulate IFN-gamma and IL-12Rbeta2 chain expression in the absence of costimulation. They exhibit prominent growth characteristics and increased survival after activation, likely related to their persistent lack of CTLA-4 surface expression. The CD4+CD28- population is expanded in a subgroup of MS patients. Myelin basic protein-specific cells detected in this cell subset may play an important role in the inflammatory response within the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • Female
  • Gene Expression
  • Glycoproteins / genetics
  • Humans
  • Immunoglobulins / genetics
  • In Vitro Techniques
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Myelin Basic Protein / immunology
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, Cell Surface
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • T-Lymphocyte Subsets / immunology


  • Antigens, CD
  • CD28 Antigens
  • Glycoproteins
  • Immunoglobulins
  • Myelin Basic Protein
  • RNA, Messenger
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • Interferon-gamma