TY - JOUR
T1 - CD28 promotes plasma cell survival, sustained antibody responses, and BLIMP-1 upregulation through its distal PYAP proline motif
AU - Rozanski, Cheryl H.
AU - Utley, Adam
AU - Carlson, Louise M.
AU - Farren, Matthew R.
AU - Murray, Megan
AU - Russell, Lisa M.
AU - Nair, Jayakumar R.
AU - Yang, Zheng Yu
AU - Brady, William
AU - Garrett-Sinha, Lee Ann
AU - Schoenberger, Stephen P.
AU - Green, Jonathan M.
AU - Boise, Lawrence H.
AU - Lee, Kelvin P.
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/5/15
Y1 - 2015/5/15
N2 - In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28's prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte-induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte-induced maturation protein-1 transcriptional nexus involved in long-term survival and function.
AB - In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28's prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte-induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte-induced maturation protein-1 transcriptional nexus involved in long-term survival and function.
UR - http://www.scopus.com/inward/record.url?scp=84929104918&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1402260
DO - 10.4049/jimmunol.1402260
M3 - Article
C2 - 25833397
AN - SCOPUS:84929104918
SN - 0022-1767
VL - 194
SP - 4717
EP - 4728
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -