NDLI: Double deficiency for RORÎ³t and T-bet drives Th2-mediated allograft rejection in mice.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Schlitt, Hans J. Dahlke, Marc H. Sabet-Baktach, Manije Eggenhofer, Elke Shaotang, Zhou Malaisé, Muriel Farkas, Stefan A. Koehl, Gudrun E. Geissler, Edward K. Lantow, Margareta Rovira, Jordi Edtinger, Karoline Kroemer, Alexander Renner, Philipp
Description	Country affiliation: Germany Author Affiliation: Sabet-Baktach M ( Department of Surgery, University Hospital Regensburg, University of Regensburg, 93053 Regensburg, Germany.)
Abstract	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 RORÎ³t, 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 RORÎ³t (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 RORÎ³t 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-Î³, but not GATA-3. Thus, in the absence of T-bet and RORÎ³t, 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 RORÎ³t. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and RORÎ³t.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	8
Volume Number	191
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-10-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Allografts Immunology Graft Rejection Nuclear Receptor Subfamily 1, Group F, Member 3 Metabolism T-box Domain Proteins Th2 Cells Adoptive Transfer Animals Cell Differentiation Eosinophils Gata3 Transcription Factor Biosynthesis Heart Transplantation Adverse Effects Interferon-gamma Interleukin-4 Mice Mice, Inbred Balb C Mice, Inbred C57bl Mice, Knockout Deficiency Genetics Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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