title: Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells.
abstract: Sustained long-term antibody levels are the cornerstone of protective immunity, yet it remains unclear how they are durably maintained. A predominant theory implicates antigen-independent antibody production by a subset of long-lived plasma cells (LLPCs) that survive within bone marrow (BM). Central tenets of this model--that BM LLPCs constitute a subset defined by intrinsic biology distinct from PCs in other tissues and contribute to long-term antibody titers--have not been definitively demonstrated. We now report that long-term humoral immunity depends on the PC-intrinsic function of CD28, which selectively supports the survival of BM LLPC but not splenic short-lived PC (SLPC). LLPC and SLPC both express CD28, but CD28-driven enhanced survival occurred only in the LLPC. In vivo, even in the presence of sufficient T cell help, loss of CD28 or its ligands CD80 and CD86 caused significant loss of the LLPC population, reduction of LLPC half-life from 426 to 63 d, and inability to maintain long-term antibody titers, but there was no effect on SLPC populations. These findings establish the existence of the distinct BM LLPC subset necessary to sustain antibody titers and uncover a central role for CD28 function in the longevity of PCs and humoral immunity.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Rozanski
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.forename: Louise M
authors.initials: LM
authors.lastname: Carlson
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Nair
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
mesh_terms: D000818:Animals; D000917:Antibody Formation; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000145:classification / Q000166:cytology / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005260:Female; D056724:Immunity, Humoral; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D010950:Plasma Cells / Q000145:classification / Q000166:cytology / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013997:Time Factors
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D015850:Interleukin-6