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PMID: 8676075 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

CTLA-4 ligation blocks CD28-dependent T cell activation.

The Journal of experimental medicine ·Vol. 183 ·No. 6 ·1996-06-01 ·Pages 2541-50

Walunas TL, Bakker CY, Bluestone JA

Abstract

CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.

MeSH Terms
Abatacept Animals Antibodies, Monoclonal/pharmacology Antigens, CD Antigens, Differentiation/immunology,physiology CD28 Antigens/physiology CTLA-4 Antigen Cell Cycle Cell Line Cell Survival Cells, Cultured Cricetinae Cytokines/biosynthesis Immunoconjugates Interleukin-2/pharmacology Kinetics Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Transgenic Receptors, Antigen, T-Cell/biosynthesis,immunology T-Lymphocytes/cytology,drug effects,immunology
Chemicals
Antibodies, Monoclonal Antigens, CD Antigens, Differentiation CD28 Antigens CTLA-4 Antigen Ctla4 protein, mouse Cytokines Immunoconjugates Interleukin-2 Receptors, Antigen, T-Cell Abatacept
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Walunas T L
Department of Pathology, Ben May Institute for Cancer Research, University of Chicago, Illinois 60637, USA.
Bakker C Y
Bluestone J A
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43 references, click to expand
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.183.6.2541
Published
1996-06-01
Pages
2541-50
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2192609
Subset
IM
Grants
NCI NIH HHS · CA14599 · United States
NHLBI NIH HHS · HL0 7381-16A1 · United States
NIAID NIH HHS · P01 AI35294 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1084/jem.183.6.2541 PMC Full Text View journal details
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