Ultraviolet-B irradiation expands skin-resident CD81Foxp3 regulatory T cells with a highly activated phenotype.

Exposure to ultraviolet-B (UVB) induces the expansion of regulatory T (Treg) cells expressing proenkephalin (PENK) and amphiregulin (AREG) with a healing function in the skin. It is unclear how this UVB exposure affects the functionally distinct subsets of skin Treg cells. In this study, we have demonstrated that skin-resident CD81Treg cells expressing both Penk and Areg expanded after UVB irradiation.

Mature dendritic cells enriched in regulatory molecules may control regulatory T cells and the prognosis of head and neck cancer.

We previously reported that regulatory T (Treg) cells expressing CTLA-4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we reveal that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)-17-related molecules.

Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens.

Regulatory T (Treg) cells, which constitute about 5-10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1).

Proenkephalin regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function.

Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various immune responses. Here we report a feature of skin Treg cells expanded by ultraviolet B (UVB) exposure. We found that skin Treg cells possessing a healing function are expanded by UVB exposure with the expression of an endogenous opioid precursor, proenkephalin (PENK).

Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice.

Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance.

Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse models.

Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with Toll-like receptor (TLR)3-adjuvant and tumor antigen overcomes anti-programmed death ligand-1 (PD-L1) resistance in mouse tumor models. In the present study, 4 different ovalbumin (OVA)-expressing tumor cell lines were implanted into syngeneic mice and subjected to anti-tumor immunotherapy using ARNAX and whole OVA protein.

Type I Interferon-Independent Dendritic Cell Priming and Antitumor T Cell Activation Induced by a Lipopeptide.

-derived diacylated lipoprotein M161Ag (MALP404) is recognized by human/mouse toll-like receptor (TLR) 2/TLR6. Short proteolytic products including macrophage-activating lipopeptide 2 (MALP2) have been utilized as antitumor immune-enhancing adjuvants. We have chemically synthesized a short form of MALP2 named MALP2s (-[2,3-bis(palmitoyloxy)propyl]-CGNNDE).

Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model.

Radiotherapy induces anti-tumor immunity by induction of tumor antigens and damage-associated molecular patterns (DAMP). DNA, a representative DAMP in radiotherapy, activates the stimulator of interferon genes (STING) pathway which enhances the immune response. However, the immune response does not always parallel the inflammation associated with radiotherapy.

Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.

CD11bGr1 myeloid-derived suppressor cells (MDSCs) suppress activation/proliferation of cytotoxic T cells, thereby hindering cancer immunotherapy. MDSCs are increased after adjuvant therapy with toll-like receptor (TLR) 2 ligands, such as Pam2CSK4, in tumor-bearing mice. However, it remains unknown if the activation of TLR2 in MDSCs affects their function and the therapeutic efficacy of TLR2 ligand.

Ultraviolet B-Induced Maturation of CD11b-Type Langerin Dendritic Cells Controls the Expansion of Foxp3 Regulatory T Cells in the Skin.

Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin DCs in maintaining immunological self-tolerance after UVB exposure. After UVB exposure, dermal CD11b-type Langerin DCs upregulated surface CD86 expression, induced proliferation of Foxp3 regulatory T (Treg) cells without exogenous Ags, and upregulated a set of genes associated with immunological tolerance.

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc mice.

Background: Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway.

Methods: We established Apc Ticam1 mice and their survival was compared to survival of Apc Myd88 and wild-type (WT) mice.

The Anti-Oxidant Ergothioneine Augments the Immunomodulatory Function of TLR Agonists by Direct Action on Macrophages.

L-Ergothioneine (EGT) is a naturally-occurring amino acid which is characterized by its antioxidant property; yet, the physiological role of EGT has yet to be established. We investigated the immune-enhancing properties of EGT, and found that it acts as a potentiator of toll-like receptor (TLR) signaling. When mouse bone marrow-derived macrophages (BMDMs) were pretreated with EGT, TLR signal-mediated cytokine production was augmented in BMDMs.

Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11bLy6G intratumor myeloid cells through the TICAM-1 signaling pathway.

PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11bLy6G cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11bLy6G cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model.

STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation.

An interferon-inducing DNA sensor STING participates in tumor rejection in mouse models. Here we examined what mechanisms contribute to STING-dependent growth retardation of B16 melanoma sublines by NK cells in vivo. The studies were designed using WT and STING KO black mice, and B16D8 (an NK-sensitive melanoma line having STING) and STING KO B16D8 sublines established for this study.

Double-stranded RNA analog and type I interferon regulate expression of Trem paired receptors in murine myeloid cells.

Background: Triggering receptors expressed on myeloid cells (Trem) proteins are a family of cell surface receptors used to control innate immune responses such as proinflammatory cytokine production in mice. Trem genes belong to a rapidly expanding family of receptors that include activating and inhibitory paired-isoforms.

Results: By comparative genomic analysis, we found that Trem4, Trem5 and Trem-like transcript-6 (Treml6) genes typically paired receptors.

Live imaging of transforming growth factor-β activated kinase 1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyinosinic:polycytidylic acid.

Transforming growth factor-β activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live-imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the s.c.

Tumor cell death by pattern-sensing of exogenous RNA: Tumor cell TLR3 directly induces necroptosis by poly(I:C) in vivo, independent of immune effector-mediated tumor shrinkage.

Poly(I:C) acts on dendritic cells to induce potent antitumor effects through the production of cytokines/interferons, activation of natural killer cells and proliferation of cytotoxic T lymphocytes. In some tumor or myeloid lineages, poly(I:C) seemed to induce necroptosis in concert with a pan-caspase inhibitor by directly acting on toll-like receptor (TLR) 3 in both and models.

Adjuvant for vaccine immunotherapy of cancer--focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.

Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival.

Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo.

Ligand stimulation of the Toll-like receptors (TLRs) triggers innate immune response, cytokine production and cellular immune activation in dendritic cells. However, most TLR ligands are microbial constituents, which cause inflammation and toxicity. Toxic response could be reduced for secure immunotherapy through the use of chemically synthesized ligands with defined functions.

Pam2 lipopeptides systemically increase myeloid-derived suppressor cells through TLR2 signaling.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition.

Myeloid-derived suppressor cells confer tumor-suppressive functions on natural killer cells via polyinosinic:polycytidylic acid treatment in mouse tumor models.

Polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA, acts on myeloid cells and induces potent antitumor immune responses including natural killer (NK) cell activation. Myeloid-derived suppressor cells (MDSCs) systemically exist in tumor-bearing hosts and have strong immunosuppressive activity against antitumor effector cells, thereby dampening the efficacy of cancer immunotherapy. Here we tested what happened in MDSCs in poly I:C-treated mice.