Memory CD4+ T cells do not induce graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell–mediated immunity. Ideally, immunity to infectious agents would be transferred from donor to host without GVHD. Most donors have been exposed to common pathogens and have an increased precursor frequency of memory T cells against pathogenic antigens. We therefore asked whether memory CD62L–CD44+ CD4+ T cells would induce less GVHD than unfractionated or naive CD4+ T cells. Strikingly, we found that memory CD4 cells induced neither clinical nor histologic GVHD. This effect was not due to the increased number of CD4+CD25+ regulatory T cells found in the CD62L–CD44+ fraction because memory T cells depletion of these cells did not cause GVHD. Memory CD4 cells engrafted and responded to antigen both in vivo and in vitro. If these murine results are applicable to human alloSCT, selective administration of memory T cells could greatly improve post-transplant immune reconstitution

Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model

“…Studies of human-derived cells in humanized mice or GVHD model mice were performed using fluorescein isothiocyanateconjugated anti-HLA-A9 (OneLambda, Canoga Park, CA, USA) and anti-human lineage CD3, 14,16,19,20, and 56 (BioLegend, San Diego, CA, USA); phycoerythrin (PE)-conjugated anti-HLA A2 (BD Biosciences, San Jose, CA) and anti-CD56 (BioLegend); PE/cyanine (Cy) 5-conjugated anti-CD235ab (BD Biosciences); peridinin chlorophyll/Cy5.5-conjugated anti-CD8 (BioLegend); PE/Cy7-conjugated anti-CD3, anti-CD33 (BD Biosciences) and anti-CD38 (BD Biosciences); allophycocyanin (APC)-conjugated anti-CD3 (BioLegend) and anti-CD34 (BD Biosciences); APC/ Cy7-conjugated anti-CD19 (BioLegend); Pacific blue-conjugated anti-CD4 and anti-CD45 (BioLegend); and Alexa Fluor 405-or 647-conjugated anti-CD45 (BioLegend). Propidium iodide (PI, 1 mg/mL; Sigma-Aldrich, St. Louis, MO, USA) was added to samples to stain dead cells just before flow cytometric analysis.…”

“…We transplanted 1.0 Â 10 7 cells/mouse HLA-A2-negative or -positive PBMCs into NOG mice without irradiation (day 0). To judge whether GVHD had developed or not, blood tests, determinations of body temperature and weight, and assays of skin damage were used in previous studies [18][19][20]. In this study, to ensure as objective a determination of the onset of GVHD as possible, we decided to define GVHD onset based on minor changes in biomarker values, body temperature, and body weight, as in clinical settings (Fig.…”

Vitamin D receptor upregulation in alloreactive human T cells

“…Prior studies have demonstrated that GVHD-inducing alloreactivity is mediated primarily by naïve and possibly early memory T cells [29,30] and also may depend on ERK1/2 activation [31], which is important for IL-2 production [32]. Therefore, we developed an approach to assess VDR and p-ERK1/2 simultaneously, and examined the maturation stage dependence of VDR upregulation.…”

High Number of Memory T Cells Is Associated with Higher Risk of Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

“…They also demonstrated that CD8 þ T cells were primed early by host dendritic cells [6,18]. Other studies reported that removing CD8 þ alloreactive T cells in experimental models significantly reduced both the severity and duration of tissue damage [19][20][21].…”