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.
Highlights
IntroductionThe present data reveal a previously unknown role for CCR4 in coordinating immune cell migration to CVB-infected tissues and in controlling subsequent pancreatitis
CCR4 is a chemokine receptor that binds to CCL17 and CCL22 and is expressed by diverse cell types that drive the immune response to CVB, such as dendritic cells (DCs) and T regulatory cells (Treg)[17,18,19,20], which prompted us to ask whether CCR4 and its ligands are involved in CVB-induced disease
The present study shows that CCL17 is secreted by pancreatic cells upon CVB5 infection, which is responsible for the migration of CCR4+ cells to the pancreatic lymph nodes (PLN)
Summary
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. Th1-mediated responses contribute to tissue damage, IFN-γ-producing cells are required to control CVB replication and resolve the infection[10,11,12], whereas IL-17-producing T cells exacerbate disease[13]. We previously showed the crucial role of regulatory T cells (Tregs) in controlling exacerbated tissue inflammation induced upon CVB5 infection, which is deleterious to the host. Our data show a previously unknown role for a chemokine receptor in orchestrating key cell migration during coxsackievirus infection, which is essential for the cells to exert their function and to influence the outcome of disease
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