ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-αvβ3-Dependent Mechanisms

Although recent evidences have been unveiling the critical role of tumor microenvironments in tumor progression and metastasis, it remains unclear how resistance to various anticancer modalities is linked with the modulation of tumor microenvironments. We identified a novel mechanism whereby constitutively activated DNA damage signals in anticancer therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/chk2-and NF-κB-mediated pathways. The inhibition of tumor-specific integrin-αvβ3 improved therapeutic efficacies of anticancer drugs by stimulating endogenous host immune systems. As a mechanism of action, tumor-specific integrin-αvβ3 targets dendritic cells to facilitate phagocytosis of live resistant tumor cells, leading to impaired cross-priming of antigen-specific T lymphocytes. Our findings clarified the detrimental effects of DNA damage signals in chemosensitivity and antitumor immunity, and targeting integrin-αvβ3 has a major implication for treating patient refractory to current anticancer regimens

Interleukin-17A Deficiency Accelerates Unstable Atherosclerotic Plaque Formation in Apolipoprotein E-Deficient Mice

Objective: Interleukin-17A (IL-17A), an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial. Methods and Results: To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE^[-/-]IL-17A^[-/-]) mice. Mice were fed with high-fat diet (HFD) for either 8 or 16 weeks, both starting at ages of 6-8 weeks. We found that splenic CD4+ T cells produced high amounts of IL-17A in ApoE^[-/-] mice after HFD feeding for 8 weeks. Atherosclerosis was significantly accelerated in HFD-fed ApoE^[-/-]IL-17A^[-/-] mice compared with ApoE^[-/-] mice. Splenic CD4+ T-cells of ApoE^[-/-]IL-17A^[-/-] mice after HFD feeding for 8 weeks, but not for 16 weeks, exhibited increased IFN-γ and decreased IL-5 production. Importantly, formation of vulnerable plaque as evidenced by reduced numbers of vascular smooth muscle cells and reduced type I collagen deposition in the plaque was detected in ApoE^[-/-]IL-17A^[-/-] mice after HFD feeding for 8 weeks. Conclusions: These results suggest that IL-17A regulates the early phase of atherosclerosis development after HFD feeding and plaque stability, at least partly if not all by modulating IFN-γ and IL-5 production from CD4+ T-cells

TRAV7-2*02 Expressing CD8+ T Cells Are Responsible for Palladium Allergy

While metallic biomaterials have led to an improvement in the quality of life, metal allergies, especially to palladium (Pd), has caused a recent increase in allergic patients. Metal allergy is known to be a T cell-mediated delayed-type hypersensitivity (DTH); however, the pathogenic T cell subsets and the specific T cell receptor (TCR) have not been identified. Therefore, we attempted to identify the pathogenic T cells responsible for Pd allergy. We found that activating CD8+ T cells significantly increased and that the TRAV (TCRα variable) 7-2*02 chain skewed in Pd allergic mice. Furthermore, adoptive transfer experiments revealed that in vitro-cultured Pd-stimulated antigen presenting cells (APCs) function as memory APCs with recipient mice developing Pd allergy and that the frequency of TRAV7-2*02 increases the same as conventional Pd allergic mice. In contrast, neither proliferation of CD8+ T cells nor increasing of TRAV7-2*02 was observed in major histocompatibility complex I (MHC I)-deficient Pd-APCs transferred to mice. Taken together, we revealed that TRAV7-2*02-expressing CD8+ T cells are the pathogenic T cells for the development of Pd allergy. We also identified the CDR3 consensus motif of pathogenic TCRs as CAAXSGSWQLIF in TRAV7-2*02/TRAJ (TCRα junction)22*01 positive cells. These results suggest that the specific TCRs represent novel targets for the development of diagnostics and treatments for metal allergy

Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress.

Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, α9 integrin, which is closely associated with activated β1 integrin, and its ligand, tenascin-C, colocalize on medullary and cortical sinuses of draining lymph nodes (dLNs), which is a gate for lymphocyte exit, and that inhibition of lymphocyte egress is evident by blockade of α9 integrin-mediated signaling at dLNs. Based on in vitro analysis using lymphatic endothelial cells obtained from mice embryos, we suggested the possibility that stimulation of lymphatic endothelial cells by tenascin-C enhances S1P secretion in an α9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of α9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating α9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders

COX-2 induces T cell accumulation and IFN-γ production during the development of chromium allergy

Chromium (Cr) is commonly added into various metal alloys to improve some mechanical properties such as corrosion resistance, strength, and workability. However, Cr is also known to be a metal allergen for some individuals. Metal allergy is a T cell-mediated disease with symptoms of inflammation and swelling that involve inflammatory cytokines and prostaglandins. Hence, suppressing these inflammation paths by using COX-2 inhibitor might be useful in treating Cr allergy. In this study, mice were used with Cr-induced allergy challenge model. The mice were injected with celecoxib once per day for 7 days one hour after the challenge. Footpad samples were stained with haematoxylin and eosin (H&E), and lymphocytes were isolated from popliteal lymph nodes for the flow cytometric analysis. The results show that both prostaglandin E2 (PGE2), a known mediator of inflammation, and cyclooxygenases (COX)-2 have important roles in the development of Cr allergy. Further, COX-2 inhibitor, celecoxib, was effective in relieving swelling and inflammation in Cr-allergic mice concordant with suppression of IFN-γ production by CD8+ T cells and T cell accumulation in the lymph nodes. Therefore, the inhibition of COX-2 may be a therapeutic target for Cr allergy, and additional molecules in the PGE2 signalling pathway may also be an effective therapeutic target for the treatment of metal allergy