Mast cells are essential intermediaries in regulatory T-cell tolerance.
Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (T(Reg))-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T(Reg) cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9--a mast cell growth and activation factor--are produced by activated T(Reg) cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T(Reg) cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts.
Lu
Li-Fan
LF
Department of Microbiology & Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA.
Lind
Evan F
EF
Gondek
David C
DC
Bennett
Kathy A
KA
Gleeson
Michael W
MW
Pino-Lagos
Karina
K
Scott
Zachary A
ZA
Coyle
Anthony J
AJ
Reed
Jennifer L
JL
Van Snick
Jacques
J
Strom
Terry B
TB
Zheng
Xin Xiao
XX
Noelle
Randolph J
RJ
D000818:Animals; D002452:Cell Count; D005786:Gene Expression Regulation / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D016906:Interleukin-9 / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D012867:Skin / Q000166:cytology / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology
D016906:Interleukin-9