Critical role of CCL22/CCR4 axis in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α+ CD103+ dendritic cells

Macrophages and dendritic cells (DCs) in murine spleen are essential for the maintenance of immune homeostasis by elimination of blood-borne foreign particles and organisms. It has been reported that splenic DCs, especially CD8 alpha(+) CD103(+) DCs, are responsible for tolerance to apoptosis-associated antigens. However, the molecular mechanism by which these DCs maintain immune homeostasis by blood-borne apoptotic cell clearance remains elusive. Here, we found that the CCL22/CCR4 axis played a critical role in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8 alpha(+) CD103(+) DCs. The present results revealed that systemic administration of apoptotic cells rapidly induced a large number of CCL22 and CCR4(+) regulatory T (Treg) cells in the spleen of C57BL/6J mice. Further study demonstrated that CD8 alpha(+) CD103(+) DCs dominantly produce much higher CCL22 than CD8 alpha(+) CD103(-) DCs. Moreover, the transient deletion of CD8 alpha(+) CD103(+) DCs caused a decrease in CCL22 levels together with CCR4(+) Treg cell percentage. Subsequently, the levels of some pro-inflammatory cytokines, such as interleukin-17 and interferon-gamma in the spleen with the absence of CD8 alpha(+) CD103(+) DCs increased in response to the administration of apoptotic cells. Hence, intravenous injection of apoptotic cells induced a subsequent increase in CCL22 expression and CCR4(+) Treg cells, which contribute to the maintenance of immune homeostasis at least partially by splenic CD8 alpha(+) CD103(+) DCs.