Fyn regulates the duration of TCR engagement needed for commitment to effector function.
In naive T cells, engagement of the TCR with agonist peptide:MHC molecules leads to phosphorylation of key intracellular signaling intermediates within seconds and this peaks within minutes. However, the cell does not commit to proliferation and IL-2 cytokine production unless receptor contact is sustained for several hours. The biochemical basis for this transition to full activation may underlie how T cells receive survival signals while maintaining tolerance, and is currently not well understood. We show here that for CD8 T cells commitment to proliferation and cytokine production requires sustained activation of the Src family kinase Lck and is opposed by the action of Fyn. Thus, in the absence of Fyn, commitment to activation occurs more rapidly, the cells produce more IL-2, and undergo more rounds of division. Our data demonstrate a role for Fyn in modulating the response to Ag in primary T cells.
Filby
Andrew
A
Division of Molecular Immunology, Medical Research Council, National Institute for Medical Research, The Ridgeway, London, United Kingdom.
Seddon
Benedict
B
Kleczkowska
Joanna
J
Salmond
Robert
R
Tomlinson
Peter
P
Smida
Michal
M
Lindquist
Jonathan A
JA
Schraven
Burkhart
B
Zamoyska
Rose
R
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006649:Histocompatibility Antigens / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019000:Phosphotyrosine / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013997:Time Factors
D006649:Histocompatibility Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn