Phenotypically distinct anti-insulin B cells repopulate pancreatic islets after anti-CD20 treatment in NOD mice.

AIMS/HYPOTHESIS: Autoreactive B cells escape immune tolerance and contribute to the pathogenesis of type 1 diabetes. While global B cell depletion is a successful therapy for autoimmune disease, the fate of autoreactive cells during this treatment in autoimmune diabetes is unknown. We aimed to identify and track anti-insulin B cells in pancreatic islets and understand their repopulation after anti-CD20 treatment. METHODS: We generated a double transgenic system, the VH125.hCD20/NOD mouse. The VH125 transgenic mouse, expressing an increased frequency of anti-insulin B cells, was crossed with a human CD20 (hCD20) transgenic mouse, to facilitate B cell depletion using anti-CD20. B cells were analysed using multiparameter and ImageStream flow cytometry. RESULTS: We demonstrated that anti-insulin B cells were recruited to the pancreas during disease progression in VH125.hCD20/NOD mice. We identified two distinct populations of anti-insulin B cells in pancreatic islets, based on CD19 expression, with both populations enriched in the CD138int fraction. Anti-insulin B cells were not identified in the plasma-cell CD138hi fraction, which also expressed the transcription factor Blimp-1. After anti-CD20 treatment, anti-insulin B cells repopulated the pancreatic islets earlier than non-specific B cells. Importantly, we observed that a CD138intinsulin+CD19- population was particularly enriched after B cell depletion, possibly contributing to the persistence of disease still observed in some mice after anti-CD20 treatment. CONCLUSIONS/INTERPRETATION: Our observations may indicate why the loss of C-peptide is only temporarily delayed following anti-CD20 treatment in human type 1 diabetes.

CD200R1 promotes interleukin-17 production by group 3 innate lymphoid cells by enhancing signal transducer and activator of transcription 3 activation.

Psoriasis is a common chronic inflammatory skin disease with no cure. It is driven by the interleukin (IL)-23/IL-17A axis and type 17 T helper cells; however, recently, group 3 innate lymphoid cells (ILC3s) have also been implicated. Despite being the focus of much research, factors regulating the activity of ILC3s remain incompletely understood. Immune regulatory pathways are particularly important at barrier sites, such as the skin, gut, and lungs, which are exposed to environmental substances and microbes. CD200R1 is an immune regulatory cell surface receptor that inhibits proinflammatory cytokine production in myeloid cells. CD200R1 is also highly expressed on ILCs, where its function remains largely unexplored. We previously observed reduced CD200R1 signaling in psoriasis-affected skin, suggesting that dysregulation may promote disease. Here, we show that contrary to this, psoriasis models are less severe in CD200R1-deficient mice due to reduced IL-17 production. Here, we uncover a key cell-intrinsic role for CD200R1 in promoting IL-23-driven IL-17A production by ILC3s by promoting signal transducer and activator of transcription 3 activation. Therefore, contrary to its inhibitory role in myeloid cells, CD200R1 is required on ILC3 to promote IL-23-stimulated signal transducer and activator of transcription 3 activation, triggering optimal IL-17 production.