T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.

Human leukocyte antigen‐haploidentical transplantation for relapsed/refractory acute myeloid leukemia: Better leukemia‐free survival with bone marrow than with peripheral blood stem cells in patients ≥55 years of age

“…This approach relies mainly on immunemediated GVL effects for tumor eradication. 21,22 Several studies have assessed the impact of stem cell source (BM vs. PBSC) on allo-HCT outcomes. [23][24][25] In an individual-patient data meta-analysis using data from nine randomized trials including a total of 1111 adult patients given grafts from HLA-identical sibling after myeloablative conditioning, the use of PBSC versus BM was associated with a higher incidence of grade III-IV acute GVHD, higher incidence of chronic GVHD, and lower relapse incidence.…”

Expression and Function of Nicotinic Acetylcholine Receptors in Induced Regulatory T Cells

“…We have demonstrated that antigen-induced airway inflammation developed in immunized mice is largely dependent on CD4 + T cells [7]. Naive T cells differentiate into various helper T (Th) cell subsets, depending on their surrounding environment [8], including Th2 cells that produce IL-4 and IL-5, essential interleukins for IgE production and eosinophil activation, respectively, and Th1, Th9, and Th17 cells, which have the potential to induce allergic airway inflammation in the absence of IgE/mast cell-dependent responses [9,10]. T-cell subset-dependent inflammation could be induced in other tissues, including intestines [11].…”

TCF-1 in CD8 T cells separates GVHD from GVL

“…In order for GVHD to persist, donor T cells must proliferate in secondary lymphoid organs and target organs (Beilhack et al, 2005; Ferrara, 2014). Naive and effector T cells drive GVHD, but they are short-lived and must be replaced to maintain an alloresponse (Jiang et al, 2021; Jiang et al, 2014). Also, given that memory cells are increased among CD8 T cells when TCF-7 is lost, we hypothesized that activation and/or exhaustion of these cells may also be affected.…”