T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-γ after being transplanted into allogeneic recipients; however, IFN-γ was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4 T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORγt (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donorderived T cells into GVHD target organs plays an essential role in the development of GVHD. ␤ 2 integrins are critically important for leukocyte extravasation through vascular endothelia and for T-cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing the graft-versus-leukemia (GVL) effect. In murine allogeneic bone marrow transplantation models, we found that recipients of CD18 ؊/؊ donor T cells had significantly less GVHD morbidity and mortality compared with recipients of wild-type (WT) donor T cells. Analysis of alloreactivity showed that CD18 ؊/؊ and WT T cells had comparable activation, expansion, and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor T-cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that the in vivo GVL effect of CD18 ؊/؊ donor T cells was largely preserved, because mortality of the recipients who received transplants of CD18 ؊/؊ T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target IntroductionThe integrins are a family of heterodimeric transmembrane proteins functioning in cell-cell and cell-extracellular matrix adhesion. There are currently 18 known subunits and 8 subunits in mammals, and the integrins relevant to the immune system include those in the ␤ 1 , ␤ 2 , and ␤ 7 families. 1 The ␤ 2 family is restricted to leukocytes, and includes CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18, and CD11d/CD18. The CD11a/CD18 integrin is expressed constitutively on all leukocytes, whereas the other members of this family are restricted to various subsets. The ␤ 2 integrins bind ligands in the immunoglobulin superfamily, which are expressed by leukocytes and endothelial and epithelial cells, called intracellular adhesion molecules . 2 Integrins function in both tethering and rolling of leukocytes on endothelium through low-affinity and avidity interactions, and in the firm arrest and transmigration of leukocytes through the vascular wall. In addition to their role in leukocyte migration, integrins function in T-cell activation by stabilizing the interaction of T cells with antigen-presenting cells (APCs). The interaction of CD11a/CD18 integrin on T cells with ICAM-1 expressed on APCs is a critical component of the immunologic synapse. 3 Furthermore, integrins can provide costimulatory signals to T cells during activation, facilitating proliferation and acquisition of effector functions. 4 Absence of CD18 leads to leukocyte adhesion deficiency type 1 (LAD1). 5,6 The severity of this disease correlates with the degree of loss of CD18. 7 In the absence of CD18, severe defects in cell-cell cooperation occur, leading to a lack of homotypic lymphocyte adhesion and impaired T-cell activation accompanied by a reduced IL-2 release. 4,8,...

IntroductionType 1 diabetes is an autoimmune disease characterized by destruction of insulin-secreting pancreatic islet ␤ cells by pathogenic autoreactive T cells. 1,2 By most accounts, the nonobese diabetic (NOD) mouse represents an ideal animal model for human type 1 diabetes. 3 Female NOD mice develop insulitis at about 4 weeks of age and begin to show diabetes from about 15 weeks of age. 3 Induction of mixed chimerism via transplantation of bone marrow (BM) cells from nonautoimmune donors into autoimmune NOD mice has been shown to reverse insulitis and prevent the development of diabetes and induce tolerance to donor islet cells. [4][5][6][7][8] However, the bone marrow transplantation (BMT) procedures require nonmyeloablative total body irradiation (TBI) conditioning of the recipients. [4][5][6][7][8] The toxicity of TBI conditioning and potential for graft-versus-host disease (GVHD) prevents the application of BMT to treating type 1 diabetes and the induction of immune tolerance for islet cell transplantation. 9 This underlies the need for a radiation-free regimen. However, a radiation-free regimen that induces mixed chimerism in autoimmune mice has not been described, although administration of costimulatory blockade (anti-CD40L) has been reported to induce mixed chimerism in nonautoimmune mice. 10,11 GVHD in TBI-conditioned recipients is caused by both TBIconditioning procedures and donor T-cell attack of host epithelial tissues such as gut, skin, and liver. 12 TBI conditioning plays a critical role in initiating the tissue damage and inflammatory cascade. [13][14][15] The TBI-damaged host tissues release inflammatory cytokines (ie, tumor necrosis factor ␣ [TNF-␣], interleukin 6 [IL-6], and IL-1) and chemokines. Additionally, the gut tissue damage caused by TBI allows the release of lipopolysaccharide (LPS) from intestinal flora, which induces a wide range of secondary inflammatory actions. The inflammatory cytokines and chemokines induce the maturation and activation of host antigenpresenting cells (APCs), and the activated host APCs activate donor T cells. 16 The activated donor T cells up-regulate chemokine receptors in response to inflammatory chemokines and cytokines and migrate to inflammatory epithelial tissues and differentiate into Type-1 T helper (Th 1 ) and Type-2 cytotoxic T (Tc 1 ) cells. The Th 1 cells release inflammatory cytokines (such as interferon ␥ [IFN-␥] and TNF-␣) that further enhance local inflammation, and the Tc 1 cells attack the host tissues so that GVHD occurs. 14 GVHD in TBI-conditioned recipients can be prevented by depletion of donor T cells, but depletion of donor T cells results in a marked increase in engraftment failure. 17 Donor CD8 ϩ T cells play a critical role in facilitating donor stem cell engraftment in both murine and human BM transplant recipients, although they contribute to GVHD induction in TBI-conditioned recipients. [18][19][20] It was previously reported that donor T-cell infusion after the waning of inflammatory responses induced by TBI conditioning con...