Nature Immunology
2, 325 - 332 (2001)
doi:10.1038/86327
A point mutation in CD28 distinguishes proliferative signals from survival signalsKlaus Okkenhaug1, 2, 8, 9, Linda Wu1, 2, 9, Kristine M. Garza2, Jose La Rose2, Wilson Khoo3, Bernhard Odermatt4, Tak W. Mak1, 2, 3, 5, Pamela S. Ohashi1, 2
& Robert Rottapel1, 2, 5, 6, 71
Department of Immunology, Toronto, Ontario M5S 1A2, Canada. 2
Ontario Cancer Institute and Princess Margaret Hospital, 610 University Ave. Ontario M5G 2M9, Canada. 3
Amgen Institute, Toronto, Ontario, Canada. 4
Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland. 5
Department of Medical Biophysics, Toronto, Ontario M5S 1A2, Canada. 6
Medicine University of Toronto, Toronto, Ontario M5S 1A2, Canada. 7
St. Michaels Hospital, 80 Bond St., Toronto, Ontario M5B 1W8, Canada. 8
Present address: Ludwig Institute for Cancer Research, 91 Riding House St., London W1W 7BS, UK. 9
These authors contributed equally to this work.
Correspondence should be addressed to Robert Rottapel rottapel@uhnres.utoronto.caUpon interaction with its ligand, B7, CD28 becomes phosphorylated on tyrosines. One tyrosine in particular (Y170 in mouse CD28, Y173 in human CD28) has received much attention. This is because it permits CD28 to recruit SH2-containing signaling molecules, including phosphoinositide 3 kinase, Grb2 and Gads. Using mice we employed a transgenic approach to express a tyrosine phenylalanine mutant form of CD28 that uncouples these SH2-mediated interactions from CD28. The CD28 mutant is unable to up-regulate expression of the prosurvival protein Bcl-xL, rendering the T cells more susceptible to radiation-induced death. Nonetheless, this mutated form of CD28 still prevents the induction of anergy and promotes T cell proliferation, interleukin 2 secretion and B cell help. Thus, we describe a single point mutation within the CD28 cytoplasmic domain that uncouples signals required for proliferation and survival.
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