Osteopontin Regulates Treg Cell Stability and Function with Implications for Anti-Tumor Immunity and Autoimmunity.

Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined.

An integrin axis induces IFN-β production in plasmacytoid dendritic cells.

Type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) has been mainly studied in the context of Toll-like receptor (TLR) activation. In the current report, we reveal that, in the absence of TLR activation, the integrin-binding SLAYGLR motif of secreted osteopontin (sOpn) induces IFN-β production in murine pDCs. This process is mediated by α4β1 integrin, indicating that integrin triggering may act as a subtle danger signal leading to IFN-β induction.

Osteopontin drives KRAS-mutant lung adenocarcinoma.

Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis.

Osteopontin Promotes Protective Antigenic Tolerance against Experimental Allergic Airway Disease.

In the context of inflammation, osteopontin (Opn) is known to promote effector responses, facilitating a proinflammatory environment; however, its role during antigenic tolerance induction is unknown. Using a mouse model of asthma, we investigated the role of Opn during antigenic tolerance induction and its effects on associated regulatory cellular populations prior to disease initiation. Our experiments demonstrate that Opn drives protective antigenic tolerance by inducing accumulation of IFN-β-producing plasmacytoid dendritic cells, as well as regulatory T cells, in mediastinal lymph nodes.

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid.

Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown.

ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity.

The development of therapies for multiple sclerosis targeting pathogenic T cell responses remains imperative. Previous studies have shown that estrogen receptor (ER) β ligands could inhibit experimental autoimmune encephalomyelitis. However, the effects of ERβ-specific ligands on human or murine pathogenic immune cells, such as Th17, were not investigated.

Circulating conventional and plasmacytoid dendritic cell subsets display distinct kinetics during in vivo repeated allergen skin challenges in atopic subjects.

Upon allergen challenge, DC subsets are recruited to target sites under the influence of chemotactic agents; however, details pertinent to their trafficking remain largely unknown. We investigated the kinetic profiles of blood and skin-infiltrating DC subsets in twelve atopic subjects receiving six weekly intradermal allergen and diluent injections. The role of activin-A, a cytokine induced in allergic and tissue repair processes, on the chemotactic profiles of DC subsets was also examined.

Osteopontin expression by CD103- dendritic cells drives intestinal inflammation.

Intestinal CD103(-) dendritic cells (DCs) are pathogenic for colitis. Unveiling molecular mechanisms that render these cells proinflammatory is important for the design of specific immunotherapies. In this report, we demonstrated that mesenteric lymph node CD103(-) DCs express, among other proinflammatory cytokines, high levels of osteopontin (Opn) during experimental colitis.

Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells.

The neurosteroid dehydroepiandrosterone (DHEA) exerts a portion of its neuroprotective effects by directly interacting with the nerve growth factor (NGF) receptors TrkA and p75(NTR) to induce prosurvival signaling. DHEA is an intermediate in the biosynthesis of estrogens and androgens that affects the endocrine system and potentially increases the risk for developing estrogen- and androgen-dependent tumors. We have synthesized 17-spiro analogs of DHEA that lack estrogenic or androgenic properties and bind to and activate NGF receptors, thus exerting potent neuroprotective effects without the tumor risk.

Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell-mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice.

Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma.

Rationale: Osteopontin (OPN) is a cytokine that is upregulated in epithelial cells and macrophages in the lungs of mice during chronic allergen challenge and airway remodeling and also in lungs of patients with asthma. However, it remains unclear whether OPN has an in vivo effect on lung remodeling in allergic asthma. Based on its ability to induce smooth muscle and fibroblast proliferation and migration we hypothesize that OPN regulates lung remodeling and also affects subsequent airway hyperresponsiveness (AHR).

Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets.

Osteopontin (Opn) is important for T helper type 1 (T(H)1) immunity and autoimmunity. However, the role of this cytokine in T(H)2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse T(H)2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge.

Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes.

The ability of autoreactive T cells to provoke autoimmune disease is well documented. The finding that immunization with attenuated autoreactive T cells (T cell vaccination, or TCV) can induce T cell-dependent inhibition of autoimmune responses has opened the possibility that regulatory T cells may be harnessed to inhibit autoimmune disease. Progress in the clinical application of TCV, however, has been slow, in part because the underlying mechanism has remained clouded in uncertainty.

T cell costimulation through CD28 depends on induction of the Bcl-xgamma isoform: analysis of Bcl-xgamma-deficient mice.

The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xgamma is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xgamma-deficient (Bcl-xgamma-/-) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE).

T cell-dependent and -independent pathways to tissue destruction following herpes simplex virus-1 infection.

Viral infections can trigger tissue destruction through innate and/or adaptive immune mechanisms. Here we show that these pathways can be differentially activated after infection by different strains of the herpes simplex virus-1 (HSV-1) virus. Infection of murine corneal tissue by HSV-1 (KOS) triggers an autoreactive clone of CD4 cells that is cross-reactive with an HSV-1 epitope to initiate corneal destruction.

Cutting edge: Attenuated experimental autoimmune encephalomyelitis in eta-1/osteopontin-deficient mice.

Recent studies indicate that early T lymphocyte activation 1 (Eta-1), also known as osteopontin, is a cytokine contributing to the development of Th1 immunity. In the present report, the role of Eta-1 in experimental autoimmune encephalomyelitis (EAE), a disease associated with Th1 immunity, was examined by analysis of disease progression in Eta-1-deficient (Eta-1-/-) mice. Although incidence and onset of peptide-induced EAE were found to be similar in Eta-1-/- and Eta-1+/+ mice, Eta-1-/- mice displayed significantly lower mean maximal clinical score and faster recovery without spontaneous relapses.