Dendritic cells and regulatory T cells expressing CCR4 provide resistance to coxsackievirus B5-induced pancreatitis

Abstract

Type B coxsackieviruses (CVB) are enteroviruses responsible for a common infectious myocarditis and pancreatitis. DCs and regulatory T cells (Tregs) are key players in controlling virus replication and regulating the immune response and tissue damage, respectively. However, the mechanisms underlying cellular migration to target tissues remain unclear. In the present study, we found that CVB5 infection induced CCL17 production and controlled the migration of CCR4+ DCs and CCR4+ Tregs to the pancreatic lymph nodes (pLN). CVB5 infection of CCR4−/− mice reduced the migration of the CD8α+ DC subset and reduced DC activation and production of IFN-β and IL-12. Consequently, CCR4−/− mice presented decreased IFN-γ-producing CD4+ and CD8+ T cells, an increased viral load and more severe pancreatitis. In addition, CCR4−/− mice had impaired Treg accumulation in pLN as well as increased T lymphocyte activation. Adoptive transfer of CCR4+ Tregs but not CCR4− Tregs was able to regulate T lymphocyte activation upon CVB5 infection. The present data reveal a previously unknown role for CCR4 in coordinating immune cell migration to CVB-infected tissues and in controlling subsequent pancreatitis. These new insights may contribute to the design of future therapies for acute and chronic infection of non-polio enteroviruses.

Dynamic Monitoring of Immunoinflammatory Response Identifies Immunoswitching Characteristics of Severe Acute Pancreatitis in Rats

“…Macrophages are the main inflammatory cells involved in the pathogenesis of SAP, secreting inflammatory cytokines such as IL-1β and TNF-α, and the number and activation of macrophages determine the severity of SAP ( 28 , 53 , 54 ). Dendritic cells are potent antigen-presenting cells that drive both adaptive and innate immunity, secreting inflammatory cytokines including TNF-α and IL-6 ( 55 , 56 ). It was hypothesized that the increase in the number of intestinal macrophages and dendritic cells at 1–3 h could be related to the activation of pancreatic enzymes in pancreatic cells, which led to a large number of immune cells activated and chemoattracted to the intestine, further activating the intestinal innate immune cells, and ultimately resulting in an enhanced inflammatory response.…”

CCL17‐CCR4 axis contributes to the onset of vitiligo in mice

“…The expression of CCL17 and CCR4 has also been shown in Tregs 32 and dendritic cells (DCs). 33 Therefore, it is important to determine whether the difference in the progression of vitiligo is caused by the balance between effector T cells and Treg cells or the depletion of immunogenic DCs. In this article, the mouse vitiligo model was induced by adoptive transfer of PMEL CD8 + T cells.…”

Physiological levels of 25‐hydroxyvitamin D3 induce a suppressive CD4+ T cell phenotype not reflected in the epigenetic landscape

“…However, we did not observe a difference in PD-1 or ICOS expression upon vitamin D3 treatment in both FOXP3 high and FOXP3 low T cells (Figure 4K,L). CCR4 is highly expressed on most immunosuppressive Treg cells 50,51 and plays a dominant mediating Treg migration to the skin. In our hands, there was no difference on CCR4 expression upon vitamin D3 supplementation independent of FOXP3 expression (Figure 4M,N).…”