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Like all herpesviruses, cytomegaloviruses (CMVs) code for many immunomodulatory proteins including chemokines. The human cytomegalovirus (HCMV) CC chemokine pUL128 has a dual role in the infection cycle. On one hand, it forms the pentameric receptor-binding complex gHgLpUL(128,130,131A), which is crucial for the broad cell tropism of HCMV. On the other hand, it is an active chemokine that attracts leukocytes and shapes their activation. All animal CMVs studied so far have functionally homologous CC chemokines. In murine cytomegalovirus (MCMV), the CC chemokine is encoded by the m131/m129 reading frames. The MCMV CC chemokine is called MCK2 and forms a trimeric gHgLMCK2 entry complex. Here, we have generated MCK2 mutant viruses either unable to form gHgLMCK2 complexes, lacking the chemokine function or lacking both functions. By using these viruses, we could demonstrate that gHgLMCK2-dependent entry and MCK2 chemokine activity are independent functions of MCK2 in vitro and in vivo. The gHgLMCK2 complex promotes the tropism for leukocytes like macrophages and dendritic cells and secures high titers in salivary glands in MCMV-infected mice independent of the chemokine activity of MCK2. In contrast, reduced early antiviral T cell responses in MCMV-infected mice are dependent on MCK2 being an active chemokine and do not require the formation of gHgLMCK2 complexes. High levels of CCL2 and IFN-γ in spleens of infected mice and MCMV virulence depend on both, the formation of gHgLMCK2 complexes and the MCK2 chemokine activity. Thus, independent and concerted functions of MCK2 serving as chemokine and part of a gHgL entry complex shape antiviral immunity and virus dissemination. Author summary: Studies on immunomodulatory proteins of herpesviruses have strongly contributed to understanding antiviral immune responses elicited during infection and to defining targets for intervention during herpesvirus infections. CC chemokines of cytomegaloviruses have been shown to shape the viral cell tropism and antiviral immune responses, yet, their modes of action are not really understood. Here, we used well-defined mutants of the MCMV chemokine MCK2 to exemplarily dissect the role of a CMV CC chemokine in viral dissemination and antiviral innate and adaptive immune responses. We could show that the chemokine activity and the entry function of MCK2 are independent players in the MCMV infection of the mouse. As cytomegaloviruses are discussed as potential vaccine vectors which may be programmed to elicit specific CD8+ T cell responses and combat specific pathogens, it is important to understand the contribution of immunomodulatory proteins to vector-induced immune responses. Specifically, in infections of Rhesus macaques with Rhesus CMV (RhCMV), the viral CC chemokine has been shown to drastically shape the immune response to vaccine antigens. Our detailed analysis of the dual roles of a CMV CC chemokine may further help to decide whether CMV vaccine vectors should express an intact viral CC chemokine or not. [ABSTRACT FROM AUTHOR]