Cre-driven tdTomato expression unexpectedly confers resistance to peripheral but not central lupus in dLckCre mice

The Cre-driven tdTomato reporter system is widely used to visualize gene expression and cellular dynamics. Here we tested the impact of the tdTomato reporter system on the progression of both central and peripheral manifestations of systemic lupus erythematosus (SLE) in dLckCre mice. We crossed dLckCre mice with ROSA26^floxed ^{^-} ^{Stop-tdTomato} mice to generate conditional dLck-driven tdTomato reporter mice (DT mice). Then, SLE models were induced by pristane injection in DT mice or by crossing DT mice with B6/lpr mice. Central and peripheral manifestations of SLE were assessed. Surprisingly, we found that DT mice exhibited a significant reduction in the progression of peripheral manifestations of SLE, evidenced by decreased severity of lymph node and splenic lesions, and improved renal pathology. However, DT mice showed similar central manifestations of SLE as control mice, evidenced by similar behavioral performance, CD4⁺ T cell infiltration in the choroid plexus, and microglial activation in the hippocampus. Flow cytometry revealed a significant reduction in the proportion of double-negative (DN) T cells in the peripheral blood of DT mice. Immunofluorescence analysis confirmed no significant differences in microglial morphology or choroid plexus CD4⁺ T cell infiltration between DT lupus mice and control mice. Notably, over 80 % of the infiltrating lymphocytes in the choroid plexus of lupus mice were CD4⁺ T cells. Adoptive transfer experiments further confirmed that these ectopically aggregated CD4⁺ T cells in the choroid plexus constitute a key pathogenic factor driving the onset and progression of neuropsychiatric SLE (NPSLE). Thus, conditional tdTomato expression alleviated peripheral but not central manifestations of SLE in dLckCre mice, suggesting a diverse role of dLck-labeled T lymphocytes in SLE development. Our results also provide additional evidence supporting the existence of a distinct separation mechanism between peripheral and central manifestations of SLE.