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.

Keywords: cell therapy; graft versus host disease; graft versus tumor; t cells subsets; tissue resident memory t cell.

Figure 1

Overview of T Cells Differentiation Pathways. The cytokine and transcription factors (TFs) niche dictates T cell differentiation in spite of the stimulation of T cell receptor signaling pathways. The prototypical cytokines and TFs that regulate each T cell subset differentiation fate are depicted. These cytokines and TFs that influence T cell differentiation have effects on the development of multiple T cell subsets, such as interleukin-6 (IL-6) is essential for T helper type 22 (Th22), T follicular helper (Tfh), and T helper 17 (Th17) cell development.

Figure 2

Overview of GVHD Pathogenesis. The gut and other issues are damaged during irradiation or chemotherapy, leading to the release of various DAMPs, PAMPs, and inflammatory cytokines. These DAMPs, PAMPs, and cytokines activate both host and donor antigen-presenting cells (APCs), which then activate the donor T cells. The APCs are also secreting various cytokines that promotes T cell differentiation toward different T cell subsets including T helper type 1 (Th1), T helper type 2 (Th2), T helper type 17 (Th17), T helper type 9 (Th9), and regulatory T cells (Tregs). Activated Th1 and Th17 T cells are able to secrete various pro-inflammatory cytokines including IFNγ, IL-17, IL-22 leading to apoptosis of cells in target tissues, mainly in the gut, liver, and skin, which can be alleviated by anti-inflammatory cytokine producing Th2, Th9 and Treg cells, such as IL-33-producing Th9.