Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells

Abstract

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (T(EM)) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of T(EM) to cause GVHD is that T(EM) lack CD62L and CCR7, which are instrumental in directing naive T cells (T(N)) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus T(EM) should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for T(N)-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on T(EM) did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that T(EM) fail to induce GVHD because of inefficient trafficking to LN and PP.

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

“…16,17 In contrast, other studies suggested that knockout of b7 was insufficient to modify intestinal GVHD, 18 and that blocking entry to specific secondary lymphoid organs (either peripheral lymph nodes or Peyer's patches) had no effect on GVHD, suggesting redundancy in secondary lymphoid tissue compartments. 19,20 Drawing general conclusions from these individual studies is difficult because of differences in the immunology of GVHD specific to the individual mouse models of HCT used in each of these separate studies. The evidence does support the theory that acute GVHD is initiated by allogeneic activation in secondary lymphoid tissue, with the induction of a specific trafficking phenotype dependent on the location of the secondary lymphoid tissue.…”

Cytokines in Graft-versus-Host Disease

“…This beneficial effect is termed "graftversus-leukemia" (GVL). The relative contributions of memory T cells to GVHD and GVL were discussed elsewhere (1). However, the effect is not specific to malignant cells, and simultaneous damage and destruction of healthy cells and tissues via the same or similar mechanisms give rise to GVHD.…”

New perspectives on the biology of acute GVHD

“…61 However, although the secondary lymphoid organs are the likely location for the interaction of APCs and T cells, they are not obligatory for the development of GVHD. 62 Mediators of GVHD Donor T cells are the critical mediators of acute GVHD regardless of the type of antigen severity (Figure 2). Evidence suggests that alloreactive donor T cells consist of several subsets with different stimuli responsiveness, activation thresholds and effector functions.…”