A point mutation in CD28 distinguishes proliferative signals from survival signals.
Upon 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.
Department of Immunology, University of Toronto, Ontario M5S 1A2, Canada.
K
K
Okkenhaug
L
L
Wu
K M
KM
Garza
J
J
La Rose
W
W
Khoo
B
B
Odermatt
T W
TW
Mak
P S
PS
Ohashi
R
R
Rottapel
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018106:CD28 Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division; D002470:Cell Survival; D017635:Clonal Anergy; D015870:Gene Expression; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014443:Tyrosine / Q000737:chemistry; D051020:bcl-X Protein; D018909:src Homology Domains
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D007136:Immunoglobulins; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases