Memory CD4+ T cells do not induce graft-versus-host disease
Britt E. Anderson, … , Mark J. Shlomchik, Warren D. Shlomchik
Britt E. Anderson, … , Mark J. Shlomchik, Warren D. Shlomchik
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):101-108. https://doi.org/10.1172/JCI17601.
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Article Immunology

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.

Authors

Britt E. Anderson, Jennifer McNiff, Jun Yan, Hester Doyle, Mark Mamula, Mark J. Shlomchik, Warren D. Shlomchik

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AutoMACS- and FACS-sorted CD25-depleted memory T cells do not cause GVHD...
AutoMACS- and FACS-sorted CD25-depleted memory T cells do not cause GVHD. Donor B10.D2 spleen cells enriched for CD4+ T cells using BioMag beads were stained with biotinylated anti-CD62L and anti-CD25 mAb’s, followed by staining with SA-beads. Cells were separated into CD25–CD62L– (negative [neg] fraction) and CD25+CD62L+ (positive [pos] fraction) cells using an AutoMACS. Phenotype of presort CD4+ T cells is shown in (a). Phenotype of CD25–CD62L– negative fraction (memory cells) is shown in (b). CD25+CD62L+ cells (positive fraction) were sorted on a FACStar cell sorter to purify CD25– (c) and CD62L+CD44– cells (d). Reanalysis of the sorted population is not available. BALB/c mice were lethally irradiated and reconstituted with 8 × 106 B10.D2 T cell–depleted BM alone (thin dashed line, n = 5) or with 1.5 × 106 unfractionated B10.D2 CD4+ T cells (thin solid line, n = 10), 2.5 × 105 CD4+CD25– naive T cells (thick solid line, n = 5), or 106 CD4+CD25– memory T cells (thick dashed line, n = 4). Incidence of GVHD (e). P < 0.0002 and P < 0.003 for difference between recipients of CD25– memory and total CD4 and CD25– naive CD4 cells, respectively. Average clinical disease score for mice affected with GVHD (f). *P < 0.02 (all time points) for CD25– memory versus total CD4. P < 0.01 on days 19–43 after transplant for recipients of CD25– memory versus naive CD4 cells. Pathology scoring from representative mice (g). #P < 0.007 and P < 0.014 for recipients of CD25– memory versus total and CD25– naive CD4 cells, respectively.