TGF-β-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance.
Regulatory B (Breg) cells have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-T cell immunoglobulin domain and mucin domain-1 and anti-CD45RB antibody treatment results in tolerance to full MHC-mismatched islet allografts in mice by generating Breg cells that are necessary for tolerance. Breg cells are antigen-specific and are capable of transferring tolerance to untreated, transplanted animals. Here, we demonstrate that adoptively transferred Breg cells require the presence of regulatory T (Treg) cells to establish tolerance, and that adoptive transfer of Breg cells increases the number of Treg cells. Interaction with Breg cells in vivo induces significantly more Foxp3 expression in CD4(+) CD25(-) T cells than with naive B cells. We also show that Breg cells express the TGF-β associated latency-associated peptide and that Breg-cell mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Breg cells, like Treg cells, demonstrate preferential expression of both C-C chemokine receptor 6 and CXCR3. Collectively, these findings suggest that in this model of antibody-induced transplantation tolerance, Breg cells promote graft survival by promoting Treg-cell development, possibly via TGF-β production.
Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Kang Mi
KM
Lee
Ryan T
RT
Stott
Gaoping
G
Zhao
Julie
J
SooHoo
Wei
W
Xiong
Moh Moh
MM
Lian
Lindsey
L
Fitzgerald
Shuai
S
Shi
Elsie
E
Akrawi
Ji
J
Lei
Shaoping
S
Deng
Heidi
H
Yeh
James F
JF
Markmann
James I
JI
Kim
D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D023001:Transplantation Tolerance
C498126:CCR6 protein, mouse; C515188:Cxcr3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054399:Receptors, CCR6; D054367:Receptors, CXCR3; D016212:Transforming Growth Factor beta
Breg cells; TGF-β; Tolerance; Transplant; Treg cells