PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

CT-M8 Mice: A New Mouse Model Demonstrates That Basophils Have a Nonredundant Role in Lupus-Like Disease Development.

Tissue-specific mouse models are essential tools to decipher the role of each cell compartment and/or their expressed genes in the pathophysiology of diseases. Here, we describe a new knock-in mouse model allowing expression of both the fluorescent protein tdTomato and the CRE recombinase selectively in the basophil compartment under the control of the Mcpt8 gene. These "CT-M8" mice did not show any abnormalities in their peripheral distribution of major immune cell populations nor their basophil function. CT-M8 mice allowed the identification of basophils by immunofluorescence and flow cytometry and basophil-specific Cre-mediated floxed gene deletion. Breeding of our CT-M8 mice with the ROSA26flox-stop-DTA mice led to the generation of basophil-deficient mice with no detectable abnormalities in other cell compartments. These mice were then used to document basophil involvement in systemic lupus erythematosus (SLE) pathophysiology since we previously reported by transient depletion of these cells during the course of an ongoing disease that they support and amplify autoantibody production in two distinct lupus-like mouse models (Lyn-/- and pristane-induced). Here, constitutive basophil deficiency prevented pristane-induced lupus-like disease development by limiting autoantibody titers and renal damages. Therefore, basophils have a nonredundant role in pristane-induced lupus-like disease and are involved in both its induction and amplification. This CT-M8 new mouse model will allow us to finely decipher the role of basophils and their expressed genes in health and disease.