Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective and potentially curative treatment for a variety of hematologic malignancies. However, graft-versus-host disease (GVHD) is a major obstacle that limits wide application of allo-HSCT, despite the development of prophylactic strategies. Owing to experimental and clinical advances in the field, GVHD is characterized by disruption of the balance between effector and regulatory immune cells, resulting in higher inflammatory cytokine levels. A reduction in regulatory T cells (Tregs) has been associated with limiting recalibration of inflammatory overaction and maintaining immune tolerance. Moreover, accumulating evidence suggests that immunoregulation may be useful for preventing GVHD. As opposed to CD4+ Tregs, the CD8+ Tregs population, which constitutes an important proportion of all Tregs, efficiently attenuates GVHD while sparing graft-versus-leukemic (GVL) effects. CD8+ Tregs may provide another form of cellular therapy for preventing GVHD and preserving GVL effects, and understanding the underlying mechanisms that different from those of CD4+ Tregs is significant. In this review, we summarize preclinical experiments that have demonstrated the role of CD8+ Tregs during GVHD and attempted to obtain optimized CD8+ Tregs. Notably, although optimized CD8+ Tregs have obvious advantages, more exploration is needed to determine how to apply them in the clinic.

TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation

“…Research has also been performed in the context of hematopoietic stem cell transplantation. In these in vivo mice studies, it was suggested that TNFR2+CD8+Tregs can preferentially target allogeneic T cells and thus effectively treat GvHD and rejection ( 56 , 57 ). However, as in CD4+ T cells, TNFα-TNFR2 expression and signaling within the CD8+ population is varied.…”

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

“…In addition, MSCs ameliorate GVHD through expansion of Tregs, especially the CD8 + Tregs ( 116 – 118 ). Unlike CD4 + Tregs, CD8 + Tregs suppress GVHD while preserving GVL activity ( 21 – 23 ). In clinic, third party, ex-vivo expanded, MSCs co-injection in a high risk, mismatched, unrelated-donor HCT reduced the severity of GVHD ( 119 ).…”

“…In addition, cellular therapy such as infusion of Tr1 can prevent GVHD while exerting GVL activity in pre-clinical models ( 16 – 18 ) and can maintain alloreactive responses without causing GVHD in humans ( 19 , 20 ). Moreover, CD8 + Tregs can enhance GVL activity while suppressing GVHD ( 21 – 23 ). In this review, we focus on the approaches that can maintain donor T cells in lymphohematopoietic tissue and augmentation of tissue PD-L1 mediating protection to prevent GVHD while preserving GVL activity.…”