The role of NK cells in transplant tolerance and rejection
Final Report Abstract
Innate cell populations such as Natural Killer cells and γδ T cells are emerging as important effector cells in transplantation, as they have recently been shown to be contributors to both early alloimmune responses and ischemia reperfusion injury. In this context our previous studies show that NK cells, contingent upon their cytokine-dependent activation status, become potent effector cells in acute allograft rejection and tolerance induction. With the help of this funding, we have shown that NK cells and γδ T cells are functionally heterogeneous populations, which play distinct roles in alloimmune responses and early IRI based on their regulation by hallmark transcription factors such as T-bet, Eomesodermin (Eomes) and RORγt. Importantly, we further demonstrate that innate effector cells in transplantation can be classified into protective and proinflammatory effector cell subsets according to transcription factor-dependent regulation. The identification of specific innate cell populations mediating transplant protection or damage may have significant clinical implications and may lead to the development of new therapeutic strategies to improve long-term transplant outcomes.
Publications
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(2011) Humanized tumor mice - a new model to study and manipulate the immune response in advanced cancer therapy. Int J Cancer 129:2194-220
Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A, Männel DN, Ortmann O, Kroemer A, Brockhoff G
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(2012) Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 3:297
Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, Baan CC, Dahlke MH, Hoogduijn MJ
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(2013) A color-coded reporter model to study the effect of immunosuppressants on CD8+ T-cell memory in antitumor and alloimmune responses. Transplantation 95:54-62
Rovira J, Sabet-Baktach M, Eggenhofer E, Lantow M, Koehl GE, Schlitt HJ, Campistol JM, Geissler EK, Kroemer A
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(2013) Double deficiency for RORγt and T-bet drives Th2-mediated allograft rejection in mice. J Immunol. 191:4440- 4446
Sabet-Baktach M, Eggenhofer E, Rovira J, Renner P, Lantow M, Farkas SA, Malaisé M, Edtinger K, Shaotang Z, Koehl GE, Dahlke MH, Schlitt HJ, Geissler EK, Kroemer A
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(2013) Heart grafts tolerized through third-party multipotent adult progenitor cells can be re-transplanted to secondary hosts with no immunosuppression. Stem Cells Transl Med Stem Cells Transl Med. 2:595-606
Eggenhofer E, Popp FC, Mendicino M, Silber P, van’t Hof W, Renner P, Hoogduijn MJ, Pinxteren J, van Rooijen N, Geissler EK, Deans R, Schlitt HJ, Dahlke MH
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(2013) Unconventional RORγt+ T cells drive hepatic ischemia reperfusion injury. J Immunol. 191:480-487
Eggenhofer E, Rovira J, Sabet-Baktach M, Groell A, Scherer MN, Dahlke MH, Farkas SA, Loss M, Koehl GE, Lang SA, Melter M, Schlitt HJ, Geissler EK, Kroemer A
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(2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 16:1180-1191
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M
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(2014) KLRG1+ natural killer cells protect against pulmonary metastatic disease by immunosurveillance. Oncoimmunology 2014 Apr 8;3:e28328
Renner P, Rovira J, Klein C, Schlitt HJ, Geissler EK, Kroemer A
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(2014) KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma. J Immunol. 192(4):1954-1961
Malaisé M, Rovira J, Renner P, Eggenhofer E, Sabet-Baktach M, Lantow M, Lang SA, Koehl GE, Farkas SA, Loss M, Agha A, Campistol JM, Schlitt HJ, Geissler EK, Kroemer A
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(2015) CD27low natural killer cells prolong allograft survival in mice by controlling alloreactive CD8+ T Cells in a T-bet-dependent manner. Transplantation 99:391-399
Lantow M, Eggenhofer E, Sabet- Baktach M, Renner P, Rovira J, Koehl GE, Schlitt HJ, Geissler EK, Kroemer A
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(2016) Cyclosporine A inhibits the T-bet-dependent antitumor response of CD8(+) T cells. Am J Transplant. 16(4):1139-1147
Rovira J, Renner P, Sabet-Baktach M, Eggenhofer E, Koehl GE, Lantow M, Lang SA, Schlitt HJ, Campistol JM, Geissler EK, Kroemer A
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(2016) RORγt(+) IL-22-producing NKp46(+) cells protect from hepatic ischemia reperfusion injury in mice. J Hepatol. 64(1):128-134
Eggenhofer E, Sabet-Rashedi M, Lantow M, Renner P, Rovira J, Koehl GE, Schlitt HJ, Geissler EK, Kroemer A
