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Cutting Edge |
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* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Departments of
Medicine and
Pathology, Harvard Medical School, and
Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; and Departments of
¶ Hematology and
|| Immunology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom
Although CTLA-4 (CD152) has potent inhibitory effects on T cell
function, the signaling events affected by this coreceptor remain to be
fully defined. Mitogen-activated protein kinases (MAPK) extracellular
signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) act as
crucial regulators of multiple aspects of cell function. Ab ligation
studies have reported an inhibitory effect of CTLA-4 on TCR-induced ERK
and JNK activation. In this study, we have re-examined the specificity
of CTLA-4 inhibition of MAPKs by using natural ligand with ex
vivo-purified CD4+ T cells deficient in CD80 and CD86
(double knockout), or CTLA-4, CD80, and CD86 (triple knockout).
Under these conditions, CTLA-4 ligation was found to up-regulate and
sustain JNK activation, while inhibiting ERK activity. At the same
time, JNK activation could not account for CTLA-4 induction of TGF-
production. Our findings demonstrate that CTLA-4 cosignaling is more
complex than previously appreciated, with an ability to differentially
regulate members of the MAPK family in T cells.
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