Double deficiency for RORγt and T-bet drives Th2-mediated allograft rejection in mice.
Although Th1, Th2, and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. To precisely address this, we used mice genetically modified for the Th1 and Th17 hallmark transcription factors T-bet and RORγt, respectively, which allowed us to study the alloreactive role of each subset in an experimental transplant setting. We found that in a fully mismatched heterotopic mouse heart transplantation model, T cells deficient for T-bet (prone to Th17 differentiation) versus RORγt (prone to Th1 differentiation) rejected allografts at a more accelerated rate, indicating a predominance of Th17- over Th1-driven alloimmunity. Importantly, T cells doubly deficient for both T-bet and RORγt differentiated into alloreactive GATA-3-expressing Th2 cells, which promptly induced allograft rejection characterized by a Th2-type intragraft expression profile and eosinophilic infiltration. Mechanistically, Th2-mediated allograft rejection was contingent on IL-4, as its neutralization significantly prolonged allograft survival by reducing intragraft expression of Th2 effector molecules and eosinophilic allograft infiltration. Moreover, under IL-4 neutralizing conditions, alloreactive double-deficient T cells upregulated Eomesodermin (Eomes) and IFN-γ, but not GATA-3. Thus, in the absence of T-bet and RORγt, Eomes may salvage Th1-mediated alloimmunity that underlies IL-4 neutralization-resistant allograft rejection. We summarize that, whereas Th17 cells predictably promote allograft rejection, IL-4-producing GATA-3(+) Th2 cells, which are generally thought to protect allogeneic transplants, may actually be potent facilitators of organ transplant rejection in the absence of T-bet and RORγt. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and RORγt.
Department of Surgery, University Hospital Regensburg, University of Regensburg, 93053 Regensburg, Germany.
Manije
M
Sabet-Baktach
Elke
E
Eggenhofer
Jordi
J
Rovira
Philipp
P
Renner
Margareta
M
Lantow
Stefan A
SA
Farkas
Muriel
M
Malaisé
Karoline
K
Edtinger
Zhou
Z
Shaotang
Gudrun E
GE
Koehl
Marc H
MH
Dahlke
Hans J
HJ
Schlitt
Edward K
EK
Geissler
Alexander
A
Kroemer
D019264:Adoptive Transfer; D064591:Allografts / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation; D004804:Eosinophils / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
C491198:Eomes protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma