Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease

Abstract

Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4 and CD8 T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rg mice. CD4 T cells and, to a lesser extent, CD8 T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4 T cells also supported the activation and proliferation of CD8 T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4 T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4 T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC) mice but not in MHC mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD.

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

“…Finally, along with the impact of Th17 coinjection, results from the first set of our experiments (PBMC versus Th17 coinjection, 4 different donors) also suggested significant interdonor variability in xGVHD severity and lethality. This finding is in accordance with previous reports from our group [34] and others [29]. Compared with mouse-to-mouse allogeneic models of aGVHD characterized by fixed genetic and immunologic disparities between donors and recipients (within a determined model), this xGVHD model uses human PBMC donors with high genetic diversity.…”

“…Over the past several decades, humanized murine models of xenogeneic GVHD (xGVHD) have been developed via the injection of human peripheral blood mononuclear cells (PBMCs) into severely immunodeficient NOD/Shi-scid IL2rg-null (NOG) or NOD/LtSz-scid IL2rg-null (NSG) mice [23][24][25][26][27][28][29][30][31][32]. These models are T cell dependent, and main triggers of T cell activation and expansion are xenogeneic MHC (H-2) class I and class II molecules [23,30,33,34] and xenogeneic costimulatory signals [27,35].…”

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

“…Presumably, this cytokine is acting on donor human effector T cells as host murine leukocytes in NSG mice do not express functional IL-2 receptors because of the absence of the IL-2 receptor c chain, 30 and since either donor human CD4 + or CD8 + T cells are sufficient to mediate GVHD in humanized NSG mice. 27,31,32 Consistent with this, the administration of low-dose IL-2 in allogeneic and humanized mouse models of GVHD results in the activation of donor effector T cells, 33,34 which circumvent any potential clinical benefits imparted by the expanded Treg cell population in these mice. 34 Notably, the co-administration of IL-10 with IL-2 can limit the expansion of effector T cells and increases survival in humanized mice with GVHD.…”

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

“…Analysis of liver, small intestine and skin revealed that all humanized NSG mice had histological evidence of GVHD (leukocyte infiltration, apoptosis and/or tissue damage). Although the leukocyte infiltrates in these tissues were not assessed, previous studies have confirmed infiltrates comprise hCD45 + leukocytes [14] predominantly hCD3 + T cells [33,34], comprising hCD4 + and hCD8 + T cells [35]. Of note, histological evidence of GVHD was more apparent in humanized mice with clinical GVHD compared to those with subclinical GVHD.…”

“…To this end, the current study provided the opportunity to examine differences in humanized mice with subclinical versus clinical GVHD, and to determine factors that correspond with clinical GVHD development. However, the lung and bone marrow are also affected in the humanized NSG mouse model of GVHD [14,35]. Thus, future studies could also compare these tissues in humanized NSG with subclinical and clinical GVHD.…”