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

doi:10.1084/jem.188.1.205

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J. Exp. Med., Volume 188, Number 1, July 1, 1998 205-210

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

By Francesca Fallarino,^* Patrick E. Fields,^* and Thomas F. Gajewski^*^§

From the ^* Department of Pathology, the 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 proposedto explain the inhibitory activity of CTLA4: competition for B7-1and B7-2 binding by CD28; sequestration of signaling moleculesaway from CD28 via endocytosis; delivery of a signal that antagonizesa CD28 signal; and delivery of a signal that antagonizes a T cellreceptor (TCR) signal. As three of these potential mechanismsinvolve functional antagonism of CD28, an experimental model wasdesigned to determine whether CTLA4 could inhibit T cell functionin the absence of CD28. TCR transgenic/recombinase activatinggene 2-deficient/CD28-wild-type or CD28-deficient mice were generatedand immunized with an antigen-expressing tumor. Primed T cellsfrom both types of mice produced cytokines and proliferated inresponse to stimulator cells lacking B7 expression. However, whereasthe response of CD28^+/+ T cells was augmented by costimulation with B7-1, the responseof the CD28^/ T cells was strongly inhibited. This inhibition was reversedby monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 canpotently inhibit T cell activation in the absence of CD28, indicatingthat antagonism of a TCR-mediated signal is sufficient to explainthe inhibitory effect of CTLA4.

Key words: T lymphocytes; costimulation; cytotoxic T lymphocyte antigen 4; B7; transgenic/knockout

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