The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

Abstract

We have examined how the host environment influences the graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor T cells induce significant GVL when administered in large numbers to established mixed chimeras (MC). However, when using limiting numbers of T cells, we found that late transfer to MC induced less GVL than did early transfer to freshly irradiated allogeneic recipients. Late donor T cell transfer to MC was associated with marked accumulation of anti-host CD8 cells within the spleen, but delayed kinetics of differentiation, reduced expression of effector molecules including IFN-␥, impaired cytotoxicity, and higher rates of sustained apoptosis. Furthermore, in contrast to the spleen, we observed a significant delay in donor CD8 cell recruitment to the bone marrow, a key location for hematopoietic tumors. donor T cell alloreactivity can be exploited to generate a powerful anti-leukemia effect, a phenomenon termed the graft-vs-leukemia (GVL) response (1, 2). Unfortunately, under conditions in which donor T cells are transferred immediately to lethally irradiated recipients, GVL responses are often associated with the development of graft-vs-host disease (GVHD). Delaying the timing of donor T cell administration by 2-3 wk may reduce the risk of GVHD in full allogeneic chimeras and still permit the induction of GVL, but by 4 -5 wk, graft-vs-host (GVH) reactivity cannot be induced (3, 4). In sharp contrast, the GVL response remains intact when donor T cells are infused (at Ͼ8 wk) into established mixed chimeras (MC), where hematopoietic elements from both the donor and recipient are present at the time of transfer (5-7). This finding relates to the continued presence of large numbers of host hematopoietic APCs, which are required for maximal priming of donor T cells recognizing recipient class I (7) and class II (5) following MHC-mismatched transplantation.Although high numbers of donor T cells activated in MC do not cause GVHD, they do so readily upon transfer to secondary, irradiated allogeneic recipients (8). Moreover, the application of a local or systemic TLR stimulus allows such donor T cells to cause local or systemic GVHD, respectively (8). These studies indicate that donor leukocyte infusion (DLI)-derived GVH-reactive T cell populations activated in MC have no absolute, intrinsic functional defect. Rather, these and other data (9 -14) argue that extrinsic factors such as inflammation within the host environment are critical for the recruitment of activated T cells to the epithelial target tissues and hence the development of GVHD. It is still not known, however, whether antihost CTL arising in established MC or freshly irradiated allogeneic (TBI-allo) recipients are fully equivalent in terms of functional activity and their capacity to induce GVL. Potentially important differences between the two host environments include the duration of direct Ag presentation by professional APC, the levels of lymphopenia-induced proliferation, the extent of suppression m...

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