Influence of RCMV-encoded vXCL1 on XCR1+ DC

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Cytomegaloviruses (CMV) use multiple strategies to modulate the immune response. One of these strategies is the expression of virus-encoded chemokines that interfere with the hosts chemokine network which plays an important role in initiating and organizing leukocyte trafficking. The English and Berlin isolates of rat CMV (MuHV-8) encode the so far only known viral gamma-chemokine. Its similar sequence to the endogenous rat, mouse, and human gamma-chemokine XCL1 resulted in its designation as viral XCL1 (vXCL1). To better understand vXCL1 function and investigate a putative competition with the host chemokine, expression of host XCL1 as well as binding of both chemokines to XCR1 was characterized. Rat XCL1 is mostly secreted by CD8+ T cells, NKT cells and NK cells as has been shown for human and mouse XCL1. Both host rat XCL1 and vXCL1 have chemokine-like properties, bind to the corresponding receptor XCR1 and attract exclusively CD4- rat DC that express XCR1. Hence, they function similarly. The receptor XCR1 is expressed on about 80% of splenic CD4- XCR1+ rat DC. Both viral XCL1 and human XCL1 are selective agonists that only activate their species-specific receptors rXCR1 and hXCR1, respectively. In contrast, host rat XCL1 is an agonist that activates both receptors. Viral XCL1 appears to be a super agonist that exhibits superior binding to rXCR1 than the endogenous rXCL1 chemokine. To further study the interaction between vXCL1 and XCR1 in rodents an xcr1 knockout rat was generated to study receptor function in the context of viral infection. In the current proposal, we will initially characterize the knockout rat and examine its response to infection. We plan to investigate if vXCL1 only activates rat XCR1 or if there is cross reactivity or antagonistic activity to XCR1 of different species. Further, we intend to infect XCR1+ DC and analyze their infection capacity. We then plan to infect animals and analyze host XCL1 expression upon infection using wild-type, vxcl1 mutant and revertant viruses. We speculate that vXCL1 attracts XCR1+ CD4- DC to benefit viral dissemination or to impair cross-presentation to circumvent cytotoxic immune responses exerted by CD8+ T lymphocytes. To examine this, we will characterize an IE1 immunodominant epitope, identify an expressed MHC allele presenting a viral peptide and ultimately test if vXCL1 is involved in blocking cross-presentation.