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.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies raised against nuclear antigens and whose production is promoted by autoreactive T follicular helper (TFH) cells. Basophils, by accumulating in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms to be defined. Here, we demonstrate that a functional relationship between TFH cells and basophils occurs in SLO during lupus pathogenesis. On SLE patient blood basophils, PD-L1 expression was upregulated and associated with TFH and TFH2 cell expansions and with disease activity. In two distinct lupus-like mouse models, TFH cell pathogenic accumulation, maintenance and function, and disease activity were dependent on basophils and their expressions of PD-L1 and IL-4. Our study establishes a direct link between basophils and TFH cells in the SLE context that promotes autoreactive IgG production and lupus nephritis pathogenesis. Altering the basophil/TFH cell axis in the SLE context may represent a promising innovative intervention strategy in SLE.