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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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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Memory CD4+ T cells do not cause GVHD. Naive and memory T cells were pur...
Memory CD4+ T cells do not cause GVHD. Naive and memory T cells were purified as described in Methods. After gating on CD4+ T cells (a), cells were sorted into CD62L+CD44– naive and CD62L–CD44+ memory fractions (b). Reanalyses of sorted populations are shown in (c). BALB/c mice were lethally irradiated and reconstituted with 8 × 106 B10.D2 T cell–depleted BM alone (thin dashed line, n = 9) or with 107 B10.D2 total spleen cells (thin solid line, n = 25), 106 naive T cells (thick solid line, n = 20), or 106 memory T cells (thick dashed line, n = 10). Data are combined from two independent experiments. GVHD incidence and mean clinical score are shown in d and e. Statistical comparisons are as follows: (d). P < 0.0001 for GVHD incidence in recipients of memory CD4 versus spleen cells or naive CD4 cells. (e) For clinical score, *P < 0.05 (time points 1–3) and ‡P < 0.01 (time points 4–6) for recipients of naive versus total spleen cells; †P < 0.05. §P < 0.001 (time points 2–10) for recipients of memory versus total spleen cells. P < 0.0001 for recipients of memory versus naive cells at all time points. BM control mice and BM plus memory cell groups did not get GVHD, but the clinical score lines were offset for clarity. Pathology scores from representative mice are shown in (f). Mean scores are indicated by horizontal bars. ††P < 0.005 and P < 0.0004 for recipients of memory versus total (unfractionated) spleen cells and memory versus naive CD4 cells, respectively.