Increased CD4+Foxp3+ T cells in BAFF-transgenic mice suppress T cell effector responses.
The cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm is particularly true for B cell-dependent immune responses; however the exact role for BAFF in regulating T cell immunity is ill-defined. To directly assess the effect of BAFF upon T cells, we analyzed T cell-dependent immune responses in BAFF-transgenic (Tg) mice. We found that T cell responses in BAFF-Tg mice are profoundly compromised, as indicated by their acceptance of islet allografts and delayed skin graft rejection. However, purified BAFF-Tg effector T cells could reject islet allografts with a normal kinetic, suggesting that the altered response did not relate to a defect in T cell function per se. Rather, we found that BAFF-Tg mice harbored an increased number of peripheral CD4+Foxp3+ T cells. A large proportion of the BAFF-expanded CD4+CD25+Foxp3+ regulatory T cells (Tregs) were CD62LlowCD103high and ICAM-1high, a phenotype consistent with an ability to home to inflammatory sites and prevent T cell effector responses. Indeed, depletion of the endogenous BAFF-Tg Tregs allowed allograft rejection to proceed, demonstrating that the increased Tregs were responsible for preventing alloimmunity. The ability of BAFF to promote Treg expansion was not T cell intrinsic, as Tregs did not express high levels of BAFF receptor 3, nor did excessive BAFF trigger NF-kappaB2 processing in Tregs. In contrast, we found that BAFF engendered Treg expansion through an indirect, B cell-dependent mechanism. Thus, under certain conditions, BAFF can play a surprising anti-inflammatory role in T cell biology by promoting the expansion of Treg cells.
Walters
Stacey
S
Immunology and inflammation Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Webster
Kylie E
KE
Sutherland
Andrew
A
Gardam
Sandra
S
Groom
Joanna
J
Liuwantara
David
D
Mariño
Eliana
E
Thaxton
Jessica
J
Weinberg
Anita
A
Mackay
Fabienne
F
Brink
Robert
R
Sprent
Jonathon
J
Grey
Shane T
ST
D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D023001:Transplantation Tolerance / Q000235:genetics
D053264:B-Cell Activating Factor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C505719:TNFSF13B protein, human