Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Regulates the Size, Reactivity, and Function of a Primed pool of CD4+T cells

We examined how cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates heterogeneous CD4+T cell responses by using experimental autoimmune encephalomyelitis (EAE), a CD4+T cell-mediated disease that is subject to regulation by CTLA-4. Disease incidence and severity were used as measures of in vivo CD4+...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2000-11, Vol.97 (23), p.12711-12716
Hauptverfasser: Kuhns, Michael S., Epshteyn, Victoria, Sobel, Raymond A., Allison, James P.
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Sprache:eng
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Zusammenfassung:We examined how cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates heterogeneous CD4+T cell responses by using experimental autoimmune encephalomyelitis (EAE), a CD4+T cell-mediated disease that is subject to regulation by CTLA-4. Disease incidence and severity were used as measures of in vivo CD4+T cell responses. The frequency, cytokine production, and reactivity of primed T cells were determined from animals immunized with proteolipid protein (PLP)-139-151 (disease agonist), PLP-Q (disease antagonist), or both peptides, and treated with control or anti-CTLA-4 antibody to analyze the responding population. CTLA-4 blockade exacerbated disease in PLP-139-151-primed animals and overcame disease antagonism in coimmunized animals, but did not permit disease induction in PLP-Q-primed animals. Experimental autoimmune encephalomyelitis enhancement was associated with increased frequencies of cytokine-producing cells and increased ratios of IFN-γ to IL-4 secretors responsive to PLP-139-151. Priming with PLP-Q elicited IL-4 and IL-2, but not IFN-γ secretors cross-reactive with PLP-139-151. Strikingly, CTLA-4 blockade was found to decrease rather than increase the frequencies of cross-reactive IL-4 and IL-2 secretors. Thus, CTLA-4 engagement limits the size, but increases the breadth, of reactivity of a primed pool of CD4+T cells, consequently regulating its function.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.220423597