The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online 14 August 2006 doi:10.1084/jem.20052230
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 9, 2121-2133
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ARTICLE

 A dose-dependent requirement for the proline motif of CD28 in cellular and humoral immunity revealed by a targeted knockin mutant

Lindzy D. Friend1, Dulari D. Shah2, Christine Deppong1, Joseph Lin3, Traci L. Bricker2, Twyla I. Juehne2, Christine M. Rose2, and Jonathan M. Green2,3

1 Program in Immunology, 2 Department of Internal Medicine, and 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

CORRESPONDENCE Jonathan M. Green: jgreen{at}im.wustl.edu

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.

Abbreviation used: GC, germinal center.

L.D. Friend and D.D. Shah contributed equally to this work.


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