Critical role of regulatory T cells in Th17-mediated minor antigen-disparate rejection.
Th17-mediated immune responses have been recently identified as novel pathogenic mechanisms in a variety of conditions; however, their importance in allograft rejection processes is still debated. In this paper, we searched for MHC or minor Ag disparate models of skin graft rejection in which Th17 immune responses might be involved. We found that T cell-derived IL-17 is critical for spontaneous rejection of minor but not major Ag-mismatched skin grafts. IL-17 neutralization was associated with a lack of neutrophil infiltration and neutrophil depletion delayed rejection, suggesting neutrophils as an effector mechanism downstream of Th17 cells. Regulatory T cells (Tregs) appeared to be involved in Th17 reactivity. We found that in vivo Treg depletion prevented IL-17 production by recipient T cells. An adoptive cotransfer of Tregs with naive monospecific antidonor T cells in lymphopenic hosts biased the immune response toward Th17. Finally, we observed that IL-6 was central for balancing Tregs and Th17 cells as demonstrated by the prevention of Th17 differentiation, the enhanced Treg/Th17 ratio, and a net impact of rejection blockade in the absence of IL-6. In conclusion, the ability of Tregs to promote the Th17/neutrophil-mediated pathway of rejection that we have described should be considered as a potential drawback of Treg-based cell therapy.
Vokaer
Benoît
B
Institut d'Immunologie Médical, Université Libre de Bruxelles, Gosselies, Belgium.
Van Rompaey
Nicolas
N
Lemaître
Philippe H
PH
Lhommé
Frédéric
F
Kubjak
Carole
C
Benghiat
Fleur S
FS
Iwakura
Yoichiro
Y
Petein
Michel
M
Field
Kenneth A
KA
Goldman
Michel
M
Le Moine
Alain
A
Charbonnier
Louis-Marie
LM
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D055879:Gene Knock-In Techniques; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
C098680:Il17a protein, mouse; D020381:Interleukin-17; D015778:Minor Histocompatibility Antigens