Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells.
Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40(+)CD44(hi)effector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (alpha-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, alpha-OX40L was added to the combined treatment protocol of LF15-0195 (LF) and anti-CD45RB (alpha-CD45RB) mAb-a protocol that induced heart allograft tolerance in non-presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor-specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4(+)CD25(+)Foxp3(+) T regulatory cells (Tregs). Of note, CD25(+) T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor-primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance.
Ge
W
W
Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
Jiang
J
J
Liu
W
W
Lian
D
D
Saito
A
A
Garcia
B
B
Li
X C
XC
Wang
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology
D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors