CD4+CD28- costimulation-independent T cells in multiple sclerosis.
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.
Markovic-Plese
S
S
Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, 10 Center Drive, Bethesda, MD 20892-1400, USA.
Cortese
I
I
Wandinger
K P
KP
McFarland
H F
HF
Martin
R
R
D000328:Adult; D015703:Antigens, CD; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D015398:Signal Transduction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016176:T-Lymphocyte Subsets / Q000276:immunology
D015703:Antigens, CD; D018106:CD28 Antigens; D006023:Glycoproteins; D007136:Immunoglobulins; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D007371:Interferon-gamma