title: CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif.
abstract: 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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Rozanski
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Adam
authors.initials: A
authors.lastname: Utley
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Louise M
authors.initials: LM
authors.lastname: Carlson
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Farren
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Megan
authors.initials: M
authors.lastname: Murray
authors.affiliation: Department of Biochemistry, University at Buffalo, Buffalo, NY 14260;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Russell
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Jayakumar R
authors.initials: JR
authors.lastname: Nair
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: ZhengYu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: William
authors.initials: W
authors.lastname: Brady
authors.affiliation: Department of Biochemistry, University at Buffalo, Buffalo, NY 14260;
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Garrett-Sinha
authors.affiliation: Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63130;
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Green
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322; Department of Cell Biology, Emory University, Atlanta, GA 30322; and.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263 Kelvin.Lee@RoswellPark.org.
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D047468:Immunoprecipitation; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011392:Proline; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D015854:Up-Regulation
chemical_list: D018106:CD28 Antigens; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D011392:Proline; D000074462:Positive Regulatory Domain I-Binding Factor 1
references.citation: Mol Immunol. 2000 Apr;37(5):221-31
references.pmid: 10930629
references.citation: Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a002436
references.pmid: 20534709
references.citation: Leukemia. 1998 Apr;12(4):610-8
references.pmid: 9557621
references.citation: J Immunol. 1998 Mar 15;160(6):2706-14
references.pmid: 9510170
references.citation: Nat Rev Immunol. 2002 Feb;2(2):116-26
references.pmid: 11910893
references.citation: Nat Rev Immunol. 2005 Mar;5(3):230-42
references.pmid: 15738953
references.citation: Nat Immunol. 2013 Mar;14(3):290-7
references.pmid: 23377201
references.citation: Leuk Res. 2002 Mar;26(3):271-80
references.pmid: 11792416
references.citation: Clin Cancer Res. 1998 Jun;4(6):1521-6
references.pmid: 9626472
references.citation: Mol Cell Biol. 2009 Nov;29(21):5813-27
references.pmid: 19737919
references.citation: Blood. 2014 Jun 12;123(24):3770-9
references.pmid: 24782505
references.citation: Nat Rev Immunol. 2006 Jan;6(1):67-78
references.pmid: 16493428
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4802-7
references.pmid: 18339801
references.citation: Mol Biol Rep. 2010 Dec;37(8):3747-55
references.pmid: 20339926
references.citation: J Immunol. 2012 Sep 15;189(6):2758-67
references.pmid: 22908331
references.citation: Xenotransplantation. 2009 Nov-Dec;16(6):477-85
references.pmid: 20042047
references.citation: J Immunol. 2006 Dec 15;177(12):8620-5
references.pmid: 17142761
references.citation: Trends Immunol. 2011 Dec;32(12):595-602
references.pmid: 22001488
references.citation: Nat Rev Immunol. 2006 Oct;6(10):741-50
references.pmid: 16977339
references.citation: J Immunol. 2011 Jan 15;186(2):1011-21
references.pmid: 21148037
references.citation: Science. 1993 Jul 30;261(5121):609-12
references.pmid: 7688139
references.citation: Immunobiology. 2002 Dec;206(5):558-62
references.pmid: 12607731
references.citation: Allergol Int. 2010 Mar;59(1):1-8
references.pmid: 20186004
references.citation: J Immunol. 2014 Apr 15;192(8):3465-9
references.pmid: 24639356
references.citation: Immunity. 2006 Mar;24(3):269-81
references.pmid: 16546096
references.citation: J Immunol. 2007 Jun 1;178(11):6894-900
references.pmid: 17513738
references.citation: J Exp Med. 2011 Jul 4;208(7):1435-46
references.pmid: 21690252
references.citation: Immunity. 2001 Dec;15(6):921-33
references.pmid: 11754814
references.citation: J Exp Med. 2006 Sep 4;203(9):2121-33
references.pmid: 16908623
references.citation: J Immunol. 1987 Jun 15;138(12):4128-32
references.pmid: 3035021
references.citation: J Exp Med. 2004 Jan 5;199(1):91-8
references.pmid: 14707116
references.citation: J Clin Oncol. 2008 Jun 1;26(16):2737-44
references.pmid: 18443352
references.citation: J Immunol. 2015 Jan 1;194(1):231-42
references.pmid: 25429072
references.citation: Blood. 2003 Feb 1;101(3):1128-40
references.pmid: 12393520
references.citation: Immunity. 1998 Mar;8(3):363-72
references.pmid: 9529153
references.citation: J Exp Med. 2005 Dec 5;202(11):1471-6
references.pmid: 16314438
references.citation: J Clin Invest. 2013 Jan;123(1):432-42
references.pmid: 23241960
references.citation: Blood. 2009 Dec 10;114(25):5173-81
references.pmid: 19846886
references.citation: N Engl J Med. 2007 Nov 8;357(19):1903-15
references.pmid: 17989383
references.citation: Arthritis Rheum. 2004 Aug;50(8):2580-9
references.pmid: 15334472
references.citation: Curr Opin Immunol. 1998 Jun;10(3):252-8
references.pmid: 9638360
references.citation: Nat Immunol. 2011 Feb;12(2):151-9
references.pmid: 21217761
references.citation: Mol Cell Biol. 2009 Jul;29(13):3710-21
references.pmid: 19398586
references.citation: J Immunol. 2011 Oct 15;187(8):3931-41
references.pmid: 21918187
references.citation: Arthritis Care Res (Hoboken). 2013 Mar;65(3):476-80
references.pmid: 22949223
references.citation: J Immunol. 1996 Jun 15;156(12):4576-81
references.pmid: 8648099
references.citation: Blood. 2007 Jun 1;109(11):5002-10
references.pmid: 17311991
references.citation: Mol Cell Biol. 1997 Jul;17(7):4051-8
references.pmid: 9199340
references.citation: J Immunol. 2011 Aug 1;187(3):1243-53
references.pmid: 21715687
references.citation: Blood. 1994 Oct 15;84(8):2597-603
references.pmid: 7522634
references.citation: Immunity. 2003 Oct;19(4):607-20
references.pmid: 14563324
references.citation: Transplantation. 1996 Dec 27;62(12):1942-5
references.pmid: 8990393
references.citation: J Exp Med. 2004 Oct 18;200(8):967-77
references.pmid: 15492122
references.citation: Immunity. 1997 Mar;6(3):303-13
references.pmid: 9075931