CD4+CD28– costimulation-independent T cells in multiple sclerosis
Silva Markovic-Plese, … , Henry F. McFarland, Roland Martin
Silva Markovic-Plese, … , Henry F. McFarland, Roland Martin
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1185-1194. https://doi.org/10.1172/JCI12516.
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Article

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

Abstract

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-γ and maximally upregulate IFN-γ and IL-12Rβ2 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.

Authors

Silva Markovic-Plese, Irene Cortese, Klaus-Peter Wandinger, Henry F. McFarland, Roland Martin

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CD4+CD28– clones are CD28 costimulation–independent. (a) CD4+CD28+ and C...
CD4+CD28– clones are CD28 costimulation–independent. (a) CD4+CD28+ and CD4+CD28– clones were plated at 105 cells per well in plates precoated with a suboptimal concentration of αCD3 (0.1 μg/ml) or αCD3 + αCD28 (5 μg/ml). Cells were cultured in duplicates for 72 hours, and proliferation was assessed by pulsing cultures with 3[H]thymidine for the final 16 hours of culture. (b) CD4+CD28– and CD4+CD28+ clones were stimulated with αCD3 or αCD3 + αCD28 mAb’s. The signaling pattern was analyzed by immunoprecipitation with anti-ZAP mAb’s and subsequent immunoblotting with mAb to phosphotyrosine. CD4+CD28– clones displayed maximal phosphorylation of TCR-ζ chain p32 and p38 when stimulated in the absence of CD28 costimulation. TCC WS+3, T cell clone WS (CD28+) 3; TCC WS-1, T cell clone WS (CD28–)1; TCC WS-2, T cell clone WS (CD28–) 2.