Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells.
The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-co-stimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.
Yuan
Xueli
X
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Ansari
M Javeed
MJ
D'Addio
Francesca
F
Paez-Cortez
Jesus
J
Schmitt
Isabella
I
Donnarumma
Michela
M
Boenisch
Olaf
O
Zhao
Xiaozhi
X
Popoola
Joyce
J
Clarkson
Michael R
MR
Yagita
Hideo
H
Akiba
Hisaya
H
Freeman
Gordon J
GJ
Iacomini
John
J
Turka
Laurence A
LA
Glimcher
Laurie H
LH
Sayegh
Mohamed H
MH
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000379:methods; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D000098815:T-bet Transcription Factor
D000911:Antibodies, Monoclonal; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor