Lactate bridges mesangial cells to the differentiation of follicular helper T cells in lupus nephritis

Lupus nephritis (LN), a serious complication of systemic lupus erythematosus, is characterized by the deposition of IgG immune complexes. The generation of these autoantibodies depends on T follicular helper (Tfh) cells within secondary lymphoid organs. However, the potential contribution of Tfh cells residing within the kidney has remained unexplored. Here, our analysis of a single-cell kidney dataset from LN patients, alongside studies in humanized chimeras and kidney organoids, identifies the accumulation of renal Tfh cells. Mechanistically, self-DNA-stimulated LN-associated mesangial cells (MC) promote Tfh differentiation by inducing CNBP-mediated MPC1 deficiency, leading to increased lactate production. In turn, elevated lactate levels enhance PCAF-catalyzed BCL6 lactylation and subsequent K6- and K29-linked ubiquitination at Lys430, preventing proteasomal degradation of BCL6. Stabilization of BCL6 ultimately reinforces Tfh differentiation, amplifying renal autoimmune responses. Importantly, targeted depletion of Tfh cells mitigates disease progression in humanized chimeras. Thus, our findings reveal a tissue program of Tfh differentiation within the autoimmune kidney microenvironment, identifying a potential therapeutic target for the management of LN. T follicular helper (Tfh) cells contribute to systemic autoimmunity. However, their involvement in the pathology of lupus nephritis (LN) remains unexplored. Here, by combining single-cell analysis of LN patient tissues and humanized mouse models, the authors show that mesangial cell-derived lactate regulates Tfh cell differentiation in LN by promoting Bcl6 lactylation and subsequent stabilization via K6 and k-29-linked polyubiquitination.