The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/205/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 1, July 1, 1998 205-210

Brief Definitive Reports

B7-1 Engagement of Cytotoxic T Lymphocyte Antigen 4 Inhibits T Cell Activation in the Absence of CD28

Francesca Fallarino*,{ddagger}, Patrick E. Fields*,{ddagger}, and Thomas F. Gajewski*,{ddagger},§

From the * Department of Pathology, the {ddagger} Committee on Immunology, and the § Department of Medicine, The University of Chicago, Chicago, Illinois 60637

Ligation of cytotoxic T lymphocyte antigen 4 (CTLA4) appears to inhibit T cell responses. Four mechanisms have been proposed to explain the inhibitory activity of CTLA4: competition for B7-1 and B7-2 binding by CD28; sequestration of signaling molecules away from CD28 via endocytosis; delivery of a signal that antagonizes a CD28 signal; and delivery of a signal that antagonizes a T cell receptor (TCR) signal. As three of these potential mechanisms involve functional antagonism of CD28, an experimental model was designed to determine whether CTLA4 could inhibit T cell function in the absence of CD28. TCR transgenic/recombinase activating gene 2–deficient/CD28–wild-type or CD28-deficient mice were generated and immunized with an antigen-expressing tumor. Primed T cells from both types of mice produced cytokines and proliferated in response to stimulator cells lacking B7 expression. However, whereas the response of CD28+/+ T cells was augmented by costimulation with B7-1, the response of the CD28–/– T cells was strongly inhibited. This inhibition was reversed by monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.

Key Words: T lymphocytes • costimulation • cytotoxic T lymphocyte antigen 4 • B7 • transgenic/knockout

Address correspondence to Thomas F. Gajewski, University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637. Phone: 773-702-4601; Fax: 773-702-3163; E-mail: tfgajews{at}mcis.bsd.uchicago.edu

T. Gajewski is a recipient of a McDonnell Foundation Scholar Award in molecular oncology. This work was also supported by grant P01 AI35294-05 from the National Institutes of Health, and by a grant from Pfizer Corporation.


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