CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4 ؊/؊ ) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4 ؊/؊ mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4؊/؊ animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4 ؊/؊ mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.Chemokines and chemokine receptors are crucially involved in innate and adaptive immune responses (6). Chemokines attract leukocytes and therefore are important for lymphocyte migration and development but also for recruitment of immune cells to sites of inflammation or infection. Regarding functional aspects, chemokines were recently classified into three subfamilies: inflammatory, homeostatic, and dual-function chemokines (48). CCL17 (thymus-and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine) are assigned to the dual-function subfamily, as they are involved in T-cell development as well as in effector cell recruitment to sites of inflammation. CCL17 and CCL22 are the functional ligands of CC chemokine receptor 4 (CCR4) (31,32). CCR4 is expressed on T cells with the Th2 phenotype, Tregs, dendritic cells, macrophages, NK cells, basophils, and platelets (11). As Th2 cells express CCR4, the receptor and its ligands have been extensively studied in the context of Th2-triggered immune responses, especially concerning chronic diseases of the respiratory tract such as allergic rhinitis, bronchial asthma, or allergic aspergillosis (27,36,42,43,51,67). It could be demonstrated that blocking CCL17 as well as CCL22 by specific antibodies results in prevention of airway hyperresponsiveness and attenuates OVA-induced airway eosinophilia (26, 37).However, there is emerging evidence that CCR4 is involved in several immune reactions other than allergy and chronic airway disease. In a murine model of cardiac transplantation, CCR4-deficient recipients showed a significantly prolonged allograft survival accompanied by a reduced number of graftinfiltrating CD4 ϩ cells (30). Recent reports on different types of lymphatic neoplasm but also on other kinds of cancer such ...