Relative Contributions of B Cells and Dendritic Cells from Lupus-Prone Mice to CD4+ T Cell Polarization

Abstract

Mouse models of lupus have shown that multiple immune cell types contribute to autoimmune disease. This study sought to investigate the involvement of B cells and dendritic cells in supporting the expansion of inflammatory and regulatory CD4 T cells that are critical for lupus pathogenesis. We used lupus-prone B6.NZM2410.Sle1.Sle2.Sle3 (TC) and congenic C57BL/6J (B6) control mice to investigate how the genetic predisposition of these two cell types controls the activity of normal B6 T cells. Using an allogeneic in vitro assay, we showed that TC B1-a and conventional B cells expanded Th17 cells significantly more than their B6 counterparts. This expansion was dependent on CD86 and IL-6 expression and mapped to the lupus-susceptibility locus. In vivo, TC B cells promoted greater differentiation of CD4 T cells into Th1 and follicular helper T cells than did B6 B cells, but they limited the expansion of Foxp3 regulatory CD4 T cells to a greater extent than did B6 B cells. Finally, when normal B6 CD4 T cells were introduced into Rag1 mice, TC myeloid/stromal cells caused their heightened activation, decreased Foxp3 regulatory CD4 T cell differentiation, and increased renal infiltration of Th1 and Th17 cells in comparison with B6 myeloid/stromal cells. The results show that B cells from lupus mice amplify inflammatory CD4 T cells in a nonredundant manner with myeloid/stromal cells.

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

“…Although the same general mechanisms regulate the activation of all T-cell subtypes (effector and regulatory) it is worth emphasizing that in the lupus autoimmunity environment, there is favoritism of self-reactive effector (4, 73, 99); with the detriment of regulatory cells (17, 97, 100). One of the bases of this polarization lies in the fact that there are plasticity and reciprocity between Th17 and Treg (100-102), a balance influenced by various factors (103), and the inflammatory and autoimmunity environment of lupus favors to the side of the Th17 cells (2,79,101). Added to Th17/IL-17 axis overactivity, LN is characterized by decrease, suppression, or dysfunction of Treg cells (57, 104) and impairment of other protective factors like IL-2 (97) and IL-10 (105, 106).…”

“…Systemic lupus erythematosus (SLE) is a disease characterized by hyperreactivity to the self, with the polarization of the immune response to a proinflammatory profile (1,2), autoantibodies production (3), immune complex formation (4) and deposition in tissues (5). It also occurs with local production of inflammatory mediators, and additional recruitment of inflammatory cells, resulting in tissue damage in various organs (6).…”

Transcriptomic and Epigenetic Alterations in Dendritic Cells Correspond With Chronic Kidney Disease in Lupus Nephritis

“…These cells, regardless the subpopulation, while dysregulated are anticipated to be responsible for the tolerance breakdown resulting in autoaggression (24). Abnormalities in circulating DCs function have been linked to the systemic manifestation of lupus, throughout the interplay with both B cells (25) and T cells (26). Our previous study revealed that molecular alterations in mDCs (CD1c+) and pDCs from lupus patients significantly influence the hyperactivated B cells, mainly through secretory and expression activity [unpublished data].…”

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

“…Pbx1d-Tg mice were bred with B6.Foxp3 YFPCre mice to generate the Treg cell reporter strain, Pbx1d-Tg.Foxp3 YFPCre . For in vitro Tfh experiments, Pbx1d-Tg mice were bred with B6.IL-21 VFP mice (57) to generate the IL-21 reporter strain, Pbx1d-Tg.IL-21 VFP .…”