Elsevier

Transplant Immunology

Volume 35, March 2016, Pages 34-39
Transplant Immunology

Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells

https://doi.org/10.1016/j.trim.2016.01.005Get rights and content

Highlights

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    CD98 heavy chain (CD98hc) is crucial for the development of acute graft-versus-host disease.

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    CD98hc deficiency in T cells is involved in increasing regulatory T cells.

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    CD98hc deficiency attenuates the expression of cytotoxic T cell-related molecules.

Abstract

Graft-versus-host disease (GvHD) is a major barrier to the broader use of allogenic hematopoietic stem cell transplantation for non-malignant clinical applications. A murine model of C57BL/6 to B6D2F1 acute GvHD was employed with T lymphocytes harboring a deletion of the CD98 heavy chain (CD98hc−/−) as donor cells. The CD98hc−/− resulted in lower responses to alloantigen stimulation in a mixed leukocyte reaction assay, and prevented the mortality associated with disease progression. The percentage of donor CD8 T lymphocytes was significantly decreased, while the percentage of Foxp3-positive regulatory T cells (Tregs) in recipients was increased by CD98hc−/−. Decreased expression of FAS, FASL, ICOS, ICOSL, PD-1 and PD-L1 by donor CD8 T cells, and mRNA expression of cytotoxic T cell-related cytokines in the recipients were shown in those with CD98hc−/−. Fewer infiltrated cells are found in the lungs, liver, tongue and skin of recipients with CD98hc−/− compared with the wild type recipients. Taken together, our data indicate that T cell-specific deletion of CD98hc can contribute to the prevention of GvHD development due to the attenuation of lymphocyte migration and by increasing the generation of Treg cells. These findings are expected to make it possible to develop novel approaches for the prevention of GvHD.

Introduction

The activation of T lymphocytes is a hallmark of graft-versus-host disease (GvHD) in hematopoietic stem cell transplantation (HSCT). T cell activation is controlled by plural glycosylated transmembrane proteins, some of which are located on the surface of T lymphocytes as specific receptors. Among them, the T cell receptor and co-stimulatory molecules, including CD25, CD27, CD28, etc. are involved in signal transmission. CD98 is classified as a type II membrane glycoprotein (125-kDa), which is composed of non-glycosylated light chains (45-kDa, Slc7a5) and a glycosylated heavy chain (80-kDa, CD98hc, Slc3a2). CD98 is associated with two distinct pathways; the acceleration of amino acid transport and mediation of integrin signaling. The different domains of CD98hc are involved in these functions [1]. The light chains of CD98 are known to be important for the function as an amino acid transported, and the extracellular domain of CD98hc binds to one of several light chains. The mammalian target of rapamycin (mTOR) pathway is regulated by amino acids and governs nutrient-regulated lymphocyte function. The proliferation, survival and migration of cells are controlled by signal transduction through certain integrin A subunits, and the intracellular and transmembrane domains of CD98hc are associated with cell migration. The complete role of CD98 in the function of the immune system is still unclear, particularly with regard to its functional role in alloimmune responses mediated by T lymphocytes.

Section snippets

Objective

In the present study, we attempted to find that the transfer of lymphocyte from CD98hc knockout (CD98hc−/−) mice prevented the development of GvHD in a semi-allogeneic (parent-into-F1) cell transplantation model, and the mechanism of its action.

Animal and acute GVHD

Ten- to 12-week-old normal female C57BL/6 (B6.wild, H-2Kb) and B6D2F1 (BDF1, H-2Kb/d) mice, a cross of B6 (H-2Kb) × DBA/2 (H-2Kd) mice were obtained from Shizuoka Laboratory Animal Center (Shizuoka, Japan). All mice used in this study were maintained in our animal facility under specific pathogen-free conditions in accordance with institutional animal care policies. T cell-specific CD98hc-deficient mice (B6.CD98hc−/−, H-2Kb) were developed in our laboratory [2]. The experiment protocol was

CD98hc deletion in T lymphocytes decreases the alloantigen response and prevents GvHD

To assess the importance of CD98hc for the T lymphocyte responses, we performed the MLR assay using fluorescent dye. CD4+ and CD8+ T lymphocytes obtained from naive B6.wild type mice showed a rapid proliferative response to irradiated BDF1 splenocytes; however, in the T lymphocytes from naive B6.CD98hc−/− mice, the proliferative response was diminished to nearly 3 to 14% of the B6.wild type level (p < 0.0001; Fig. 1A). We next performed the parent to F1 GvHD experiment, in which the activated

Discussion

In this study, we aimed to evaluate the effects of CD98hc deletion in T cells in a mouse model of GvHD by assessing histopathology, proliferation pattern of lymphocyte, and expression of CTL- or Treg-related molecules. This is the first attempt to CD98hc deletion in T cell for the attenuation of acute GvHD. An improvement of all symptoms was observed in recipients after receiving splenocytes from T cell specific CD98hc−/− mouse, and included: 1) improved survival; 2) decreased number of donor

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

This study was supported in part by research grants 15K10043 and 24/02741 from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grants 26-6, 26-27 and 27-21 from the National Center for Child Health and Development.

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    Yoshiaki Nishio and Masayuki Fujino contributed equally to this work.

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