Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals.
The hypothesis that bystander inflammatory signals promote memory B cell (B(MEM)) self-renewal and differentiation in an antigen-independent manner is critically evaluated herein. To comprehensively address this hypothesis, a detailed analysis is presented examining the response profiles of B-2 lineage B220(+)IgG(+) B(MEM) toward cognate protein antigen in comparison to bystander inflammatory signals. After in vivo antigen encounter, quiescent B(MEM) clonally expand. Surprisingly, proliferating B(MEM) do not acquire germinal center (GC) B cell markers before generating daughter B(MEM) and differentiating into plasma cells or form structurally identifiable GCs. In striking contrast to cognate antigen, inflammatory stimuli, including Toll-like receptor agonists or bystander T cell activation, fail to induce even low levels of B(MEM) proliferation or differentiation in vivo. Under the extreme conditions of adjuvanted protein vaccination or acute viral infection, no detectable bystander proliferation or differentiation of B(MEM) occurred. The absence of a B(MEM) response to nonspecific inflammatory signals clearly shows that B(MEM) proliferation and differentiation is a process tightly controlled by the availability of cognate antigen.
Benson
Micah J
MJ
Department of Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH 03756, USA. Benson@IDI.Harvard.edu
Elgueta
Raul
R
Schpero
William
W
Molloy
Michael
M
Zhang
Weijun
W
Usherwood
Edward
E
Noelle
Randolph J
RJ
D000818:Animals; D000941:Antigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001973:Bromodeoxyuridine; D024201:Bystander Effect / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence
D000941:Antigens; D001973:Bromodeoxyuridine
Nature. 1997 Jul 10;388(6638):133-4
9217150
Eur J Immunol. 1991 Dec;21(12):2951-62
1748148
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4802-7
18339801
J Exp Med. 1997 Sep 15;186(6):931-40
9294147
Nature. 2000 Oct 5;407(6804):636-42
11034213
J Exp Med. 2009 Mar 16;206(3):681-9
19273623
J Immunol. 2008 Jan 1;180(1):361-71
18097037
Immunol Rev. 2006 Jun;211:295-302
16824136
Nature. 1991 Apr 11;350(6318):502-5
2014051
Blood. 2003 Jun 1;101(11):4500-4
12560217
Eur J Immunol. 1976 Jul;6(7):467-72
1086788
J Immunol. 1990 Oct 1;145(7):2183-8
2144547
Immunol Rev. 2006 Jun;211:255-68
16824133
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7396-401
16651521
J Exp Med. 2000 Apr 3;191(7):1149-66
10748233
Int Immunol. 2007 Jul;19(7):837-46
17606982
Nat Immunol. 2007 Apr;8(4):419-29
17322888
Proc Natl Acad Sci U S A. 1987 Mar;84(5):1379-83
3493491
J Immunol. 2006 Apr 15;176(8):4515-9
16585539
Proc Natl Acad Sci U S A. 1970 Nov;67(3):1398-403
5274467
Vaccine. 2008 Jan 17;26(3):430-9
18083278
Eur J Immunol. 1990 Mar;20(3):509-15
2138557
J Immunol. 2008 Aug 1;181(3):1746-52
18641311
J Exp Med. 2007 Sep 3;204(9):2103-14
17698588
Nature. 1990 Aug 23;346(6286):749-51
2388695
J Immunol. 1984 Oct;133(4):1710-5
6206131
Science. 1995 May 5;268(5211):720-2
7537388
Science. 2002 Dec 13;298(5601):2199-202
12481138
Blood. 2006 Apr 1;107(7):2806-13
16339400
J Immunol. 2008 Jan 15;180(2):1148-57
18178855
Cell. 1987 Mar 13;48(5):757-70
3493076
Eur J Immunol. 1988 Mar;18(3):355-62
3258564
Immunity. 2007 Sep;27(3):384-92
17892847
Curr Opin Immunol. 1999 Apr;11(2):172-9
10322151
Immunity. 1998 Mar;8(3):363-72
9529153
Immunity. 2007 Aug;27(2):190-202
17723214
J Exp Med. 1991 May 1;173(5):1165-75
1902502
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15517-22
18832171
Eur J Immunol. 1992 Nov;22(11):3001-11
1425924
J Immunol. 2008 Mar 15;180(6):3655-9
18322170
N Engl J Med. 2007 Nov 8;357(19):1903-15
17989383
Annu Rev Immunol. 1994;12:117-39
8011279
J Exp Med. 2004 Mar 15;199(6):775-84
15007094
J Immunol. 1982 Dec;129(6):2698-707
6982940
Vaccine. 2003 Jun 1;21 Suppl 2:S35-7
12763680
J Immunol. 1997 Feb 1;158(3):1108-15
9013949