Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL.
CD28 provides an important costimulatory signal in T cell activation that regulates multiple cellular processes including proliferation and survival. Several signal transduction pathways are activated by CD28; however, the precise biochemical mechanism by which CD28 regulates T cell function remains controversial. Retroviral gene transfer into primary T cells from TCR-transgenic, CD28-deficient mice was used to determine the specific sequences within CD28 that determine function. Discrete regions of the cytoplasmic domain of CD28 were identified that differentially regulate T cell proliferation and induction of the anti-apoptotic protein Bcl-X(L). Mutation of C-terminal proline residues abrogated the proliferative and cytokine regulatory features of CD28 costimulation while preserving Bcl-X(L) induction. Conversely, mutation of residues important in phosphatidylinositol 3-kinase activation partially inhibited proliferation but prevented induction of Bcl-X(L.) Thus the ability of CD28 to regulate proliferation and induction of Bcl-X(L) map to distinct motifs, suggesting independent signaling cascades modulate these biologic effects.
Burr
J S
JS
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Savage
N D
ND
Messah
G E
GE
Kimzey
S L
SL
Shaw
A S
AS
Arch
R H
RH
Green
J M
JM
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011392:Proline / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D051020:bcl-X Protein
D018106:CD28 Antigens; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D011392:Proline; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse