Search

Clinical trials are currently testing whether induction of haploidentical mixed chimerism (Haplo-MC) induces organ transplantation tolerance. Whether Haplo-MC can be used to treat established autoimmune diseases remains unknown. Here, we show that established autoimmunity in euthymic and adult-thymectomized NOD ([H-2.sup.g7]) mice was cured by induction of Haplo-MC under a non-myeloablative anti-thymocyte globulin-based conditioning regimen and infusion of [CD4.sup.+] T cell-depleted hematopoietic graft from [H-2.sup.b/g7] [F.sub.1] donors that expressed autoimmune-resistant [H-2.sup.b] or from [H-2.sup.s/g7] [F.sub.1] donors that expressed autoimmune-susceptible [H-2.sup.s]. The cure was associated with enhanced thymic negative selection, increased thymic Treg (tTreg) production, and anergy or exhaustion of residual host-type autoreactive T cells in the periphery. The peripheral tolerance was accompanied by expansion of donor- and host-type [CD62L.sup.-][Helios.sup.+] tTregs as well as host-type [Helios.sup.-][Nrp1.sup.+] peripheral Tregs (pTregs) and [PD-L1.sup.hi] plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type [PD-L1.sup.hi] pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and [Helios.sup.-][Nrp1.sup.+] pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-[MHC.sup.+] donor-type DCs, [PD-L1.sup.hi] host-type DCs, and the generation and persistence of donorand host-type tTregs and pTregs., Introduction Haploidentical hematopoietic cell transplantation (Haplo-HCT) has been widely applied to the treatment of hematological malignancies and nonmalignant disorders (1). Induction of haploidentical mixed chimerism (Haplo-MC) for organ transplantation immune [...]

[CD4.sup.+] T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular [CD44.sup.hi][CD62L.sup.lo][PSGL1.sup.lo][CD4.sup.+] T cells ([PSGL1.sup.lo][CD4.sup.+] T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized [MHC.sup.-/-][HLA-A2.sup.+][DR4.sup.+] murine models of cGVHD, we showed that murine and human [PSGL1.sup.lo][CD4.sup.+] T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine [PSGL1.sup.lo][CD4.sup.+] T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human [PSGL1.sup.lo][CD4.sup.+] T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human [PSGL1.sup.lo][CD4.sup.+] T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD- L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted., Introduction Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and chronic graft-versus-host disease (cGVHD) are mediated by abnormal [CD4.sup.+] T cell interaction with B cells and autoantibody deposition in [...]

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (CVHD), whereas costimulation of CD80 and PD-1 ameliorates CVHD. Here we have demonstrated that temporary depletion of donor [CD4.sup.+] T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor [CD4.sup.+] T cells increased serum IFN-[gamma] but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor [CD8.sup.+] T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor [CD8.sup.+] T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment [CD8.sup.+] T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in [CD8.sup.+] T cells depends on the presence or absence of [CD4.sup.+] T cells, the nature of the interacting receptor expressed by [CD8.sup.+] T cells, and the tissue environment in which the signaling occurs., Introduction Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma), owing to graft-versus-leukemia/lymphoma (GVL) effects mediated by alloreactive T cells. These same T [...]

Type I diabetes in both humans and nonobese diabetic (NOD) mice results from autoreactive T cell destruction of insulin-producing cells. Cure of type 1 diabetes may require both reversal of autoimmunity and regeneration of [beta] cells. Induction of chimerism via allogeneic hematopoietic cell transplantation has been shown to reestablish tolerance in both prediabetic and diabetic NOD mice. However, it is unclear whether this therapy augments [beta] cell regeneration. Furthermore, this procedure usually requires total body irradiation conditioning of recipients. The toxicity of total body irradiation conditioning and potential for graft-versus-host disease (GVHD) limit the application of allogeneic hematopoietic cell transplantation for treating type 1 diabetes. Here we report that injection of donor bone marrow and [CD4.sup.+] T cell-depleted spleen cells induced chimerism without causing GVHD in overtly diabetic NOD mice conditioned with anti-CD3/CD8 and that induction of chimerism in new-onset diabetic NOD mice led to elimination of insulitis, regeneration of host [beta] cells, and reversal of hyperglycemia. Therefore, this radiation-free GVHD preventive approach for induction of chimerism may represent a viable means for reversing type 1 diabetes. hematopoietic cell transplantation | type 1 diabetes | anti-CD3-conditioning | reversal of diabetes | reversal of autoimmunity

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell–specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142–deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142–deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses. This study identifies microRNA-142 as a central regulator of the development, homeostasis and function of regulatory T cells. Mechanistically, the miR-142-3p isoform controls regulatory T cell homeostasis and immune tolerance by attenuating IFNγ responses. [ABSTRACT FROM AUTHOR]