A dose-dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant.
Activation of naive T cells requires the integration of signals through the antigen receptor and CD28. Although there is agreement on the importance of CD28, there remains controversy on the mechanism by which CD28 regulates T cell function. We have generated a gene-targeted knockin mouse expressing a mutation in the C-terminal proline-rich region of the cytoplasmic tail of CD28. Our analysis conclusively showed that this motif is essential for CD28-dependent regulation of interleukin 2 secretion and proliferation. In vivo analysis revealed that mutation of this motif-dissociated CD28-dependent regulation of cellular and humoral responses in an allergic airway inflammation model. Furthermore, we find an important gene dosage effect on the phenotype of the mutation and provide a mechanistic explanation for the conflicting data on the significance of this motif in CD28 function.
Friend
Lindzy D
LD
Program in Immunology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Shah
Dulari D
DD
Deppong
Christine
C
Lin
Joseph
J
Bricker
Traci L
TL
Juehne
Twyla I
TI
Rose
Christine M
CM
Green
Jonathan M
JM
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D016535:Bronchial Hyperreactivity / Q000276:immunology; D018106:CD28 Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation; D004306:Dose-Response Relationship, Immunologic; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D011392:Proline / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D007074:Immunoglobulin G; D007376:Interleukin-2; D051020:bcl-X Protein; D011392:Proline