Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.

Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8+ tissue-resident memory T cells (TRM cells) require active transforming growth factor-β1 (TGF-β) for epidermal residence. Here we found that integrins αvβ6 and αvβ8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-β. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required αvβ6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-β, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-β by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication.

Chronicgraft-versus-host disease (cGVHD) is an increasingly common cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Relative to acute GVHD (aGVHD), much less is understood about cGVHD. Using the B10.D2 3 BALB/c murine cGVHD model, which shares critical pathologic features with human cGVHD, we find that radiation-resistant host T cells regulate cGVHD. We initially observed that recipients lacking all lymphocytes developed accelerated and more severe cGVHD. Using genetically deficient recipients, we determined that ␣␤ ؉ CD4 ؉ T cells were required to regulate cGVHD. Increased cGVHD severity was not due to the absence of T cells per se. Rather, the potency of regulation was proportional to host T-cell receptor (TCR) diversity. Only CD4 ؉ CD25 ؉ , and not CD4 ؉ CD25 ؊ , host T cells ameliorated cGVHD when added back, indicating that host T cells acted not via host-versus-graft activity or by reducing homeostatic proliferation but by an undefined regulatory mechanism. Thus, preparative regimens that spare host CD4 ؉ CD25 ؉ T cells may reduce IntroductionChronic graft-versus-host disease (cGVHD) is an increasingly common complication of allogeneic stem cell transplantation (alloSCT). Its incidence, as high as 80% in some series, is thought to be on the rise at least in part due to the use of peripheral blood as a stem cell source, nonmyeloablative conditioning, withdrawal of immunosuppression to induce antitumor activity, better supportive care allowing longer survival, and the number of patients receiving donor leukocyte infusions. [1][2][3][4][5][6][7] Even with a wide range of therapeutic options including agents that target tumor necrosis factor-␣ (TNF-␣) and the interleukin-2 (IL-2) receptor, cGVHD and the infectious complications of its management are major causes of late mortality for alloSCT recipients. 8 Acute GVHD (aGVHD) and cGVHD are traditionally diagnosed primarily by time of onset, with cGVHD occurring after day 100 after transplantation. 9 However, cGVHD has distinct clinicopathologic features and is often diagnosed based on these features regardless of time of onset. 10 aGVHD typically presents with inflammatory skin, gastrointestinal, and/or hepatic disease, while cGVHD is characterized by cutaneous fibrosis, involvement of exocrine glands, myositis, and hepatic disease. 9,10 Often cGVHD occurs in patients who have had prior aGVHD, although de novo cGVHD without aGVHD is not uncommon and the relationship between the two is unclear. In particular, de novo cGVHD occurs with some frequency after delayed leukocyte infusion given for the treatment of relapsed leukemia. Importantly, both de novo cGVHD and that which emerges from prior aGVHD share clinicopathologic features. Donor T cells cause cGVHD, but much about the pathobiology of cGVHD is unknown. Most animal research on GVHD has been performed in murine models of aGVHD, with donor and recipient strains partially or fully mismatched at the major histocompatibility complex (MHC) locus. Broadly speaking, disease in th...

The graft-versus-leukemia (GVL) effect, mediated by donor T cells, has revolutionized the treatment of leukemia. However, effective GVL remains difficult to separate from graft-versus-host disease (GVHD), and many neoplasms are GVL resistant. Murine studies aimed at solving these problems have been limited by the use of leukemia cell lines with limited homology to human leukemias and by the absence of loss-of-function leukemia variants. To address these concerns, we developed a GVL model against murine chronic-phase chronic myelogenous leukemia (mCP-CML) induced with retrovirus expressing the bcr-abl fusion cDNA, the defining genetic abnormality of chronic-phase CML (CP-CML). By generating mCP-CML in gene-deficient mice, we have studied GVL T-cell effector mechanisms. mCP-CML expression of Fas or tumor necrosis factor (TNF) receptors is not required for CD8-mediated GVL. Strikingly, maximal CD4-mediated GVL requires cognate interactions between CD4 cells and mCP-CML cells as major histocompatibility complex-negative (MHC II ؊/؊ ) mCP-CML is relatively GVL resistant. Nevertheless, a minority of CD4 recipients cleared MHC II ؊/؊ mCP-CML; thus, CD4 cells can also kill indirectly. CD4 GVL did not require target Fas expression. These results suggest that CP-CML's GVL sensitivity may in part be explained by the minimal requirements for T-cell killing, and GVL-resistance may be related to MHC II expression. (Blood.