|
Signal
Transduction Events in T Lymphocytes 
The response to antigen by T lymphocytes involves complex molecular interactions
involving multiple receptors. We are studying how receptors initiate signal
transduction events that regulate T cell responses. The T cell antigen
receptor (TCR) complex interacts with members of the Src, Syk and Tec
families of cytoplasmic protein tyrosine kinases (PTKs). We are attempting
to understand how the TCR regulates these PTKs as well as the functions
of their substrates.
CD45, a receptor protein tyrosine phosphatase (RPTP) expressed on hematopoietic
cells, regulates TCR signal transduction by influencing the activity of
Src PTKs. Dimerization of CD45 negatively regulates its function by blocking
the PTP catalytic site. This contrasts with the activating effects of
ligands for most receptors. Inactivation of this inhibitory mechanism
for CD45 leads to lymphoproliferation and autoimmunity. Our current studies
are focused on regulation of CD45 dimerization and the effects of disrupting
the dimerization-mediated inhibitory mechanism.
TCR stimulation alone is insufficient to activate T cells. Other interactions
with molecules on an antigen presenting cell (APC) are required. CD28,
a receptor on T cells, binds to the B7 molecules on APCs and induces a
signal involving the Akt and other kinases that activates the c-Rel and
AP-1 transcription factors. These factors then bind to a transcriptional
element in the interleukin-2 and other lymphokine genes. We are studying
CD28 signaling and its contribution to T cell differentiation/activation.
Selected Publications:
Weiss, A. and D. R. Littman (1994). Signal transduction by lymphocyte
antigen receptors. Cell 76:263-274.
Majeti, R., Z. Xu, T.G. Parslow, J.L. Olson, D.I. Daikh, N. Killeen, and
A. Weiss. (2000). An inactivating point mutation in the inhibitory wedge
of CD45 causes lymphoproliferation and autoimmunity. Cell 103:1059-1070.
Kane, L.P., P.G. Andres, K.C. Howland, A.K. Abbas, and A. Weiss (2001).
Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and
IFN-g but not Th2 cytokines. Nature Immunol. 2:37-44.
Contact Information:
Email: aweiss@medicine.ucsf.edu
Phone: (415) 476-8983
Address: Box 0795, Room U 330
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
|
