E4BP4 restrains effector-memory CD8 ⁺ T cell responses in systemic lupus erythematosus

Increasing evidence shows that CD8+ T cells are the pathogenic mediators of tissue injury in systemic lupus erythematosus (SLE), sustaining the chronic inflammation through the accumulation of long-lived cytotoxic memory populations. However, the transcriptional mechanisms that prevent the aberrant differentiation of pathogenic CD8+ T cells remain poorly understood. Here, the transcription factor E4BP4 (NFIL3) was identified as a critical restraint of cytotoxic effector-memory CD8+ T cells in lupus. E4BP4 expression was reduced in CD8+ T cells from SLE patients and inversely correlated with disease activity. Using a lupus-like disease model, we found that E4BP4 deficiency accelerated disease progression, resulting in heightened autoantibody production, immune complex deposition, and renal pathology. This phenotype was associated with the systemic accumulation of cytotoxic effector-memory CD8+ T cells. Depletion of CD8+ T cells significantly ameliorated the disease phenotype, confirming the functional contribution of CD8+ T cells to lupus-like immunopathology. Competitive adoptive transfer experiments revealed that E4BP4 functions cell-intrinsically to limit the cytotoxicity and proliferation of CD8+ T cells in autoimmunity. Beyond autoimmunity, E4BP4 deficiency also resulted in an exuberant CD8+ effector-memory T cell response to Listeria monocytogenes infection, indicating a broader role for E4BP4 in limiting CD8+ T cell effector-memory responses. Collectively, these findings establish E4BP4 as a transcriptional checkpoint that restricts pathogenic CD8+ effector-memory T cell responses to maintain immune homeostasis in autoimmunity and infection.