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Published online before print October 1, 2004, 10.1073/pnas.0406168101
PNAS | October 12, 2004 | vol. 101 | no. 41 | 14859-14864


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IMMUNOLOGY
Activation of naïve CD4 T cells by anti-CD3 reveals an important role for Fyn in Lck-mediated signaling

Katsuji Sugie *, Myung-Shin Jeon {dagger}, and Howard M. Grey *, {ddagger}

Divisions of *Vaccine Discovery and {dagger}Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

Contributed by Howard M. Grey, August 23, 2004

Although there was no impairment in IL-2 secretion and proliferation of Fyn-deficient naïve CD4 cells after stimulation with antigen and antigen-presenting cells, stimulation of these cells with anti-CD3 and anti-CD28 revealed profound defects. Crosslinking of purified wild-type naïve CD4 cells with anti-CD3 activated Lck and initiated the signaling cascade downstream of Lck, including phosphorylation of ZAP-70, LAT, and PLC-{gamma}1; calcium flux; and dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT)p. All of these signaling events were diminished severely in Fyn-deficient naïve cells activated by CD3 crosslinking. Coaggregation of CD3 and CD4 reconstituted this Lck-dependent signaling pathway in Fyn-/- T cells. These results suggest that when signaling of naïve T cells is restricted to the T cell antigen receptor, Fyn plays an essential role by positive regulation of Lck activity.

Author contributions: K.S. and H.M.G. designed research; K.S. and M.-S.J. performed research; K.S., M.-S.J., and H.M.G. analyzed data; and K.S. and H.M.G. wrote the paper.

Abbreviations: PCC, pigeon cytochrome c; Tg, transgenic; TCR, T cell antigen receptor; APC, antigen-presenting cell; NFAT, nuclear factor of activated T cells; AP-1, activator protein 1; ITAM, immunoreceptor tyrosine-based activation motif.

{ddagger} To whom correspondence should be addressed. E-mail: hgrey{at}liai.org .

© 2004 by The National Academy of Sciences of the USA


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