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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Donor memory cells engraft and respond to antigenic challenge. B10.D2 mi...
Donor memory cells engraft and respond to antigenic challenge. B10.D2 mice were immunized intraperitoneally with CGG in CFA and used 3 weeks later as CD4+ cell and BM donors. ATX BALB/c mice were irradiated and reconstituted with 8 × 106 T cell–depleted BM cells with no CD4 cells (thin dashed line, n = 9), 1.5 × 106 unfractionated CD4 cells (thin solid line, n = 17), or 106 CD4+CD25– memory cells (thick line, n = 14). Incidence of GVHD (a). P < 0.001 for GVHD incidence in recipients of CD25– memory cells versus total CD4 cells. Transplanted memory cells respond to CGG (b). Thirty-seven days after the transplant, recipients and unmanipulated ATX BALB/c mice were immunized with CGG or PCC in CFA. Two weeks later, draining LN cells were collected, depleted of residual recipient cells, and rechallenged with 50 μg CGG in vitro in a standard proliferation assay. Cells were pooled from all animals (n = 3–7) of an experimental group: untransplanted ATX control, BM alone, BM plus unfractionated CD4 cells, BM plus CD25–CD4+ memory cells. Background counts (no antigen) were subtracted from plotted data. P = 0.0002 for proliferation to CGG for BM plus memory cells versus BM plus unfractionated CD4 cells. P < 0.0001 for BM plus memory cells versus BM alone. Error bars indicate standard deviation of samples run in triplicate.