Systemic lupus erythematosus is a multifactorial autoimmune disease that can affect several organs, notably the joints, skin, and kidneys, where it manifests as lupus nephritis. Its pathophysiology stems from a breakdown of immune tolerance, leading to the accumulation of autoreactive B and T lymphocytes and the production of autoantibodies directed against nuclear antigens, such as double-stranded DNA or ribonucleoproteins. These autoantibodies form circulating immune complexes that deposit in target organs, sustaining chronic inflammation and, in parallel, activating innate immune cells, including basophils, thereby fueling a deleterious amplification loop. Follicular helper T cells (TFH), which are essential for the maturation of B lymphocytes into antibody-secreting cells, play a central role in this process and are dysregulated during the disease. While the accumulation of basophils in secondary lymphoid organs was known to amplify autoantibody production, the underlying mechanisms remained to be elucidated.
To investigate this question, the team combined observations in humans with murine models of lupus, supported by co-culture experiments between basophils and CD4+ T lymphocytes. These approaches enabled direct testing of the influence of basophils on the differentiation and function of TFH cells, relying on the use of blocking antibodies targeting notably IL-4 and PD-1, as well as on transcriptional analyses by RT-qPCR of transcription factors characteristic of TFH cells (BCL6, GATA3, BATF, MAF, among others). Basophil depletion models were also used to assess their contribution in vivo.
This work demonstrates a direct functional relationship between basophils and TFH cells during lupus pathogenesis. The overexpression of PD-L1 on the surface of basophils and their production of IL-4 are associated with the expansion of TFH cells and their type 2 subpopulation (TFH2, characterized by GATA3 expression and IL-4 production), as well as with disease activity. The accumulation, maintenance, and function of pathogenic TFH cells in secondary lymphoid organs were found to depend on basophil-derived PD-L1 and IL-4, with these mediators inducing a transcriptional program favorable to TFH2 differentiation and function.
These findings establish a direct mechanistic link between basophils and TFH cells in systemic lupus erythematosus, a link that promotes autoantibody production and the development of lupus nephritis. They thus clarify the previously ill-defined role of basophils in sustaining the autoimmune response.