Targeting CXCR6+ T cell recruitment and memory in cutaneous lupus

Cutaneous lupus erythematosus (CLE) or skin lupus, is a group of autoimmune diseases that affects the skin and other tissues. T cells are a type of immune cell that can cause lupus flares in the skin. Recently, Dr. Richmond’s laboratory developed a new mouse model of CLE to more accurately study the T cell responses that occur in CLE. She and her team found that the T cells that cause skin disease in the mice have a protein on their cell surface called CXCR6, which is also present in pet dogs and people with lupus. The T cell CXCR6 connects with a protein called CXCL16 on skin cells, similar to how a lock and key fit together.

With the LRA Lupus Mechanisms and Targets Award, Dr. Richmond and her team will use their novel CLE mouse model to test whether CXCR6 directs lupus-causing T cells to stay in the skin and cause disease flares. They will also test a new treatment in pet dogs with CLE in a veterinary clinical trial to see if targeting CXCR6-CXCL16 will provide a lasting treatment response.

What this study means for people with lupus

This research will provide new information about whether specific molecules on the surface of lupus-causing immune cells could be targeted to prevent or slow lupus disease progression.

Cutaneous lupus erythematosus (CLE) is a heterogeneous group of autoimmune diseases with a broad range of skin and mucosal tissue manifestations. Like many other autoimmune diseases, CLE disproportionately affects females, and the average age of onset is 30 years. African American and Asian American patients tend to have higher disease activity/severity scores as compared to Caucasian patients, indicating racial/ethnic disparities exist. Controlling skin disease can prevent other organ involvement.
In collaboration with Dr. Ann Marshak-Rothstein, we recently published that Th2-skewed cells promoted development of cutaneous lupus lesions in mice; however, Th1-skewed cells could not induce skin manifestations. To understand which molecules may be responsible for Th2-induced skin phenotypes, we analyzed the expression of molecules known to be associated with mucosal homing. We found that Th2 cells expressed significantly more CXCR6 than their Th1 counterparts. However, there is no CXCR6-/- available on the Balb/c background. Therefore, my lab developed a novel mouse model of CLE on the B6 background that uses a model autoantigen under the control of a tetracycline response element. Adoptive transfer of transgenic CD4+ T cells that recognize the model autoantigen results in skin disease. We can model flares in these mice by introducing and reintroducing doxycycline chow. This permits inquiry of memory responses, as well as genetic requirements of the T cells themselves.
CXCR6 is a particularly intriguing target in light of several published studies: (1) CXCL16 (ligand for CXCR6) is a biomarker of lupus nephritis in juvenile SLE patients, (2) CXCL16 is upregulated in keratinocytes following UV light exposure, (3) recently 2 labs independently demonstrated that CXCR6 is expressed on CD8+ tissue resident memory T cells (Trm) in the context of the tumor microenvironment. My lab members and I queried our mouse, human and canine datasets and found that CXCR6/CXCL16 upregulation in cutaneous lupus lesions is conserved across all 3 species, making this an attractive treatment target both for its high level of conservation across species and for its potential role in maintaining Trm in the lupus disease setting.  We hypothesize that CXCR6 permits skin tropism on lupogenic T cells, and targeting CXCR6 and its ligand CXCL16 will provide a durable treatment response due to its role in maintaining Trm cells. We plan to test this hypothesis through the following specific aims:
Aim 1. Determine whether CXCR6 is required for primary disease and flares in the B6 CLE mouse model.
Aim 2. Determine whether CXCR6 and CXCL16 are increased in human CLE lesional skin across multiple clinical subtypes and races/ethnicities using a novel home-based tape stripping test kit.
Aim 3. Determine whether targeting CXCR6-CXCL16 in canine CLE is an effective treatment strategy (veterinary clinical trial).
Our long-term objective is to develop a durable CLE treatment.