Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

Abstract

Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4 ؉ effector memory T cells (T EMs ) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4 ؉ T EMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating genedeficient leukemias and using perforindeficient T cells, we demonstrate that direct cytolytic function is essential for T EM -mediated GVL, but that GVL is retained when killing via FasL, TNF-␣, TRAIL, and perforin is individually impaired. However, T EM -mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative therapy for hematologic malignancies, including acute and chronic leukemias and lymphomas. In an alloSCT, donor T cells in the allograft are critical for reconstituting T-cell immunity in the host 1 and mediate an antitumor effect called graft-versus-leukemia (GVL). [2][3][4][5] Unfortunately, donor T cells also broadly attack recipient tissues, including the skin, bowel, and liver, in a process called graft-versus-host disease (GVHD). GVHD is a major cause of morbidity and mortality in alloSCT, which greatly limits the efficacy and applicability of this life-saving therapy. GVHD is particularly severe when the donor and recipient are not fully major histocompatibility complex (MHC)-matched. This is because the precursor frequency of T cells that recognize non-self-MHC has been estimated to be at least 1000-to 10 000-fold higher than that of T cells that recognize minor histocompatibility antigen peptides presented by self-MHC. Therefore, many centers that perform transplantations using HLA-haploidentical donors rigorously deplete allograft T cells. 6,7 While this T-cell depletion is highly effective in minimizing GVHD, it essentially abrogates donor T cell-mediated immune reconstitution and GVL. Preserving the positive effects of donor T cells-GVL and immune reconstitution-without GVHD remains the central challenge in the alloSCT field.We and others have previously reported that effector memory T cells (T EMs ) do not induce GVHD in MHC-matched and MHC-mismatched models and can transfer functional T-cell memory. [8][9][10][11] This is consistent with the prior demonstration that antipathogen T-cell memory is transferred from donor to recipient in human alloSCT. [12][13][14][15][16] These data suggest a strategy wherein donor T EMs would be selectively infuse...

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

“…Effector memory CD4 ϩ T cells transferred into irradiated recipients have been shown to mediate the rejection of retrovirally induced B cell lymphoma without inducing GVHD (46). Our data support the idea that PD-L1-mediated negative regulation could represent the mechanism by which mHA-specific effector memory CD4 ϩ T cells are prevented to induce severe GVHD.…”

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…Hence, in vivo-expanded iC9 1 virus-specific T cells may be more resistant to the apoptotic signals generated by iC9 than alloreactive T cells. [34][35][36][37][38][39] Thus, iC9 activation in alloreplete T cells can selectively eliminate the alloreactive component of T cells that cause GVHD, while sparing the virus-reactive subpopulation, even when CID is administered during an active viral infection.…”

New perspectives on the biology of acute GVHD

“…Donor effector memory T cells that are non-alloreactive do not induce GVHD, yet are able to transfer functional memory 66 and mediate GVL. 70 In addition, lymphopenia-induced proliferation gives rise to cells that are similar to memory T cells and enhance the graft-vs-tumor effect after donor leukocyte injection. 71 In contrast, memory T cells that are alloreactive can cause severe GVHD.…”