T-Cell Subsets Mediate Graft-Versus-Myeloid Leukemia Responses via Different Cytotoxic Mechanisms

Document Type

Journal Article

Publication Date

1-1-2000

Journal

Biology of Blood and Marrow Transplantation

Volume

6

Issue

3

DOI

10.1016/S1083-8791(00)70005-X

Keywords

Bone marrow; Fas ligand; Graft-versus-leukemia; Perforin; T-cell subsets

Abstract

Analysis of the cytotoxic effector mechanisms by which T-cell subsets mediate graft-versus-leukemia (GVL) activity is complicated by systems that use unfractionated T cells and leukemias that express alloantigens in addition to tumor-specific antigens. In this study, we used MMB1.10, a myeloid leukemia of C57B1/6 (B6) origin, to examine the cytolytic pathways employed by syngeneic GVL-mediating, and therefore tumor antigen-specific, T-cell subsets. Wright-Giemsa staining and flow cytometric analysis indicated that MMB1.10 cells exhibited the morphology and markers most consistent with a monocytic-myeloid origin. Although reverse transcription-polymerase chain reaction analysis revealed that MMB1.10 cells expressed tumor necrosis factor (TNF) receptor types I and II, in vitro assays suggested that these cells were resistant to TNF-α-mediated cytotoxicity. For study of in vivo GVL responses, mice were challenged with MMB1.10 cells, lethally irradiated, and administered anti-Thy-1-treated (T-cell-depleted) bone marrow (ATBM) either alone or in combination with T-cell subsets from MMB1.10-presensitized mice. In regard to CD4+ donor T cells, 4 × 106 MMB1.10-presensitized wild-type (wt) cells exhibited increased GVL responses and survival values relative to tumor-challenged recipients of ATBM only. CD4+ T cells from either perforin-deficient (pfp°) or Fas ligand (FasL)-deficient (gld) mice exhibited a lower level of GVL activity but did not produce any long-term survivors. Recipients of 5 × 106 wt B6 CD8+ T cells had significantly improved survival relative to tumor-challenged mice that received ATBM only. The same dose of gld CD8+ T cells exhibited a reduced but significant level of GVL activity, whereas cells from mice that were perforin-deficient or cytotoxicity doubly deficient (cdd) (ie, lacking perform and FasL) exhibited no discernable GVL activity. Doubling the gld CD8+ T-cell dose to 107 cells resulted in further improved survival of recipients. We conclude that GVL effects mediated by CD4+ T cells can depend on either perforin- or FasL-mediated mechanisms, whereas the CD8+ T-cell subset is heavily dependent on perforin-mediated cytotoxicity.

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