Project Summary
Sensitivity to UV light affects ~80% of lupus patients and can exacerbate local skin disease and
lead to systemic disease flares. The molecular pathways predisposing lupus patients to
photosensitivity and the mechanisms driving the inflammatory responses to UV light are poorly
understood. We showed that a single exposure to UV light leads to a rapid type I interferon (IFN-
I) response in human and murine skin in vivo. That UV light is a potent stimulus of the IFN-I
response is particularly relevant as lupus patients (~75%) have a high IFN-I signature in both the
skin tissue and the peripheral blood cells, indicative of worse disease. Therefore, there is a critical
need to discover what regulates the IFN-I production in response to UV light and in lupus skin.
Recent studies showed that deficiency in VISTA result in lupus-like skin disease and accelerate
systemic disease in lupus mouse models. The observed pathologies were accompanied by an
increase in the IFN-I signature, suggesting VISTA can modulate the IFN-I response. Indeed, we
demonstrated that an agonistic anti-VISTA antibody inhibits the IFN-I response in human
monocytes. While findings that the transcriptional profile of cells from lupus patients resembles
that of murine VISTA-/- cells suggest an important role for VISTA in lupus pathogenesis, how
VISTA modulates the IFN-I response in lupus skin and in response to UV light is unknown. Here,
we hypothesize that VISTA negatively regulates the IFN-I response to UV light and that VISTA
activity in keratinocytes modulates the baseline and UV-triggered IFN-I production. To test these
hypotheses, we will pursue the following specific aims: In Aim 1, we will define how VISTA
regulates local and systemic IFN-I response to UV light in vivo. We predict that the IFN-I response
to UV light in the skin and blood of VISTA-/- mice will be of greater magnitude and/or duration,
compared to VISTA-sufficient controls. We will examine the therapeutic potential of targeting
VISTA to modulate the IFN-I response to UV light using an agonistic anti-human VISTA
monoclonal antibody in humanized VISTA knock-in mice. In Aim 2, we will characterize UV-light
triggered IFN-I production by keratinocytes and define keratinocyte VISTA function. The cellular
source and class of IFN-I in UV light exposed skin is unknown as is the function of VISTA
expressed by keratinocytes. Given the rapid IFN-b production in the skin after UV exposure, we
will investigate the contribution of keratinocytes as the likely source of IFN-Is in UV light-exposed
skin of normal and lupus mouse strains. We will also define the keratinocyte-specific VISTA
function in vivo in VISTA conditional knockout mice and in primary lupus keratinocytes.