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Review
.2022 May 23:13:907673.
doi: 10.3389/fimmu.2022.907673. eCollection 2022.

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity

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Review

Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity

Qingxiao Song et al. Front Immunol..

Abstract

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma) due to the graft-versus-leukemia (GVL) activity mediated by alloreactive T cells that can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells can cause a serious side effect, known as graft-versus-host disease (GVHD). GVHD and GVL occur in distinct organ and tissues, with GVHD occurring in target organs (e.g., the gut, liver, lung, skin, etc.) and GVL in lympho-hematopoietic tissues where hematological cancer cells primarily reside. Currently used immunosuppressive drugs for the treatment of GVHD inhibit donor T cell activation and expansion, resulting in a decrease in both GVHD and GVL activity that is associated with cancer relapse. To prevent GVHD, it is important to allow full activation and expansion of alloreactive T cells in the lympho-hematopoietic tissues, as well as prevent donor T cells from migrating into the GVHD target tissues, and tolerize infiltrating T cellsvia protective mechanisms, such as PD-L1 interacting with PD-1, in the target tissues. In this review, we will summarize major approaches that prevent donor T cell migration into GVHD target tissues and approaches that augment tolerization of the infiltrating T cells in the GVHD target tissues while preserving strong GVL activity in the lympho-hematopoietic tissues.

Keywords: PD-L1; anti-IL-2; chemokine and chemokine receptors; graft versus host disease (GVHD); graft versus leukaemia (GVL); naive T cell depletion.

Copyright © 2022 Song, Nasri, Nakamura, Martin and Zeng.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Depletion of donor CD4+ T cells and tolerogenic anti-IL-2 mAb (JES6-1) administration prevents acute GVHD while preserving GVL activity. The depletion of CD4+ T cells by anti-CD4 mAb prevented both acute and chronic GVHD while preserving GVL activity. In GVHD target tissues, depletion of CD4+ T cells allowed host tissue PD-L1 interaction with PD-1 expressed by donor CD8+ T cells to induce anergy, exhaustion and apoptosis. In lymphoid tissues, the treatment allowed PD-L1 and CD80 interactions among lymphocytes and DCs to augment expansion of CD8+ T cells that mediating GVL activity. Furthermore, CD4+ T cells help CD8+ T cellsvia their production of IL-2. Administration of tolerogenic anti-IL-2 mAb (JES6) expanded IL-10+FoxP3-CD4+ Tr1 cells in GVHD target tissues. In addition, increased expression of granzyme B and generation of TCF-1+CD8+ memory progenitors that can give rise to cytotoxic effector cells in lymphoid tissues, leading to effectively prevention of aGVHD while preserving GVL activity. Created withBioRender.com.
Figure 2
Figure 2
Summary of approaches for prevention of GVHD while preserving GVL activity. (1) Retention of donor T cells in lympho-hematopoietic tissue. (2) Depletion of naïve donor T cells and infusion of mesenchymal stem cells. (3) Augmentation of tissue PD-L1 mediated immune tolerance. Created with BioRender.com.
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