The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against ...particle‐bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune‐mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low‐dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy‐based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte‐derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle‐associated antigens in homeostasis. KC‐associated antigen presentation induces CD4 T‐cell arrest, expansion of naturally occurring Foxp3+CD25+ interleukin‐10‐producing antigen‐specific regulatory T cells (Tregs) and tolerogenic immunity. Particle‐associated tolerance induction in the liver protected mice from kidney inflammation in T‐cell‐mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune‐mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen‐specific CD4 T cells. In injured liver, infiltrating monocyte‐derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype. Conclusions: Hepatic induction of tissue‐protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases. (Hepatology 2015;62:279‐291)
Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of ...peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b+Gr-1intLy6Chi cells, mostly comprising proliferating CCR2+-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8+ T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.
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► The spleen is a crucial organ for tumor-induced tolerance ► Chemotherapy enhances the efficacy of passive immunotherapy by eliminating splenic CD11b+Gr-1int cells ► CD11b+Gr-1int splenocytes comprise CCR2+ cycling myeloid precursors that cross-tolerize Ag-specific CD8+ T lymphocytes ► CCL2 serum levels are predictive of clinical outcome in patients who respond to cancer vaccination
During their evolution, tumors exploit several mechanisms to limit immune attacks, leading to a progressive lack of tumor antigen recognition, a process of tumor-conditioned tolerance. Tolerance is thought to occur within the tumor and in the lymph nodes draining the tumor area. Bronte and colleagues unveil a tolerogenic environment in the spleen of tumor-bearing hosts. Chemotherapy-sensitive, immature monocytes are recruited to the marginal zone of the spleen by a CCL2/CCR2 axis, present tumor antigens, and tolerize tumor-specific CD8+ T cells.
IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double-deficient Th17 cells identified the Th2 transcription ...factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and it induced Stat1-independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6-deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE (Maf recognition element) motif in the IL-10 promoter. Taken together, these data reveal a novel role for c-Maf in regulating T effector development, and they suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.
Interleukin-23 (IL-23) responsive group 3 innate lymphoid cells (ILC3s) have been implicated in immune homeostasis and pathogenesis in the adult, but little is known about their roles in the newborn. ...Here we show that IL-23 promotes conversion of embryonic intestinal Lin(-)IL-23R(+)Thy1(+) cells into IL-22-producing Thy1(+)Sca-1(hi) ILC3s in vitro. Gut-specific expression of IL-23 also activated and expanded Thy1(+)Sca-1(hi) ILC3s, which produced IL-22, IL-17, interferon gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and were distinct from canonical CD4(+) lymphoid tissue inducer (LTi) cells. These ILC3s accumulated under the epithelium in intercellular adhesion molecule (ICAM)-1-positive cell aggregates together with neutrophils that disrupted the epithelium, leading to the formation of discrete intestinal erosions, bleeding, and neonatal death. Genetic and antibody depletion of ILC3s rescued the mice from neonatal death. Antibiotic treatment of pregnant mothers and offspring prolonged survival of IL-23 transgenic mice, suggesting a role for the commensal flora on ILC3-induced pathogenesis. Our results reveal a novel role for the IL-23-ILC3s axis in the pathogenesis of neonatal intestinal inflammation.
Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation ...(allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.
Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress the immune response, a definition that reflects both their origin and their function. As negative regulators of the immune ...response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. MDSC are present in cancer patients and tumor-bearing mice and are in part responsible for the inhibition of the cell-mediated immune response against the tumor. Our laboratories investigate the immunologic mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. A better understanding of MDSC biology will open new avenues for therapeutic intervention, either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in organ transplantation and alloimmune responses). In this review, we summarize some of the critical aspects of the immunoregulatory function of MDSC in cancer and transplantation and discuss their potential clinical applications.
Airway epithelium is the primary target of trachea and lung transplant rejection, the degree of epithelial injury is closely correlated with obliterative bronchiolitis development. In this study, we ...investigated the cellular and molecular mechanisms of IL-17A-mediated airway epithelial injury after transplantation.
Murine orthotopic allogeneic trachea or lung transplants were implemented in wild type or RORγt mice. Recipients received anti-IL-17A or anti-IFNγ for cytokine neutralization, anti-CD8 for CD8 T-cell depletion, or STAT3 inhibitor to suppress type 17 CD4+/CD8+ T cell development. Airway injury and graft inflammatory cell infiltration were examined by histopathology and immunohistochemistry. Gene expression of IL-17A, IFNγ, perforin, granzyme B, and chemokines in grafts was quantitated by real-time RT-PCR.
IL-17A and IFNγ were rapidly expressed and associated with epithelial injury and CD8 T-cell accumulation after allotransplantation. Depletion of CD8 T cells prevented airway epithelial injury. Neutralization of IL-17A or devoid of IL-17A production by RORγt deficiency improved airway epithelial integrity of the trachea allografts. Anti-IL-17A reduced the expression of CXCL9, CXCL10, CXCL11, and CCL20, and abolished CD8 T-cell accumulation in the trachea allografts. Inhibition of STAT3 activation significantly reduced IL-17A expression in both trachea and lung allografts; however, it increased IFNγ expression and cytotoxic activities, which resulted in the failure of airway protection.
Our data reveal the critical role of IL-17A in mediating CD8 T effector response that causes airway epithelial injury and lung allograft rejection, and indicate that inhibition of STAT3 signals could drive CD8 T cells from Tc17 toward Tc1 development.
To determine the site and mechanism of suppression by regulatory T (Treg) cells, we investigated their migration and function in an islet allograft model. Treg cells first migrated from blood to the ...inflamed allograft where they were essential for the suppression of alloimmunity. This process was dependent on the chemokine receptors CCR2, CCR4, and CCR5 and P- and E-selectin ligands. In the allograft, Treg cells were activated and subsequently migrated to the draining lymph nodes (dLNs) in a CCR2, CCR5, and CCR7 fashion; this movement was essential for optimal suppression. Treg cells inhibited dendritic cell migration in a TGF-β and IL-10 dependent fashion and suppressed antigen-specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and to dLNs is required for Treg cells to differentiate and execute fully their suppressive function.
We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we ...analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4(+)CD25(+)CD62L(high) T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4(+)CD25(+) Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3(+)CD4(+)CD25(+) Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.
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