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(+) 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-gamma to IL-4 secretors responsive to PLP-139-151. Priming with PLP-Q elicited IL-4 and IL-2, but not IFN-gamma 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.
Kuhns
M S
MS
Howard Hughes Medical Research Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA.
Epshteyn
V
V
Sobel
R A
RA
Allison
J P
JP
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D060908:CTLA-4 Antigen; D048429:Cell Size; D006224:Cricetinae; D003429:Cross Reactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D005260:Female; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D015847:Interleukin-4; D000069594:Abatacept; D007371:Interferon-gamma