Lupus-prone (NZBxNZW)F1 mice exhibit decreased ability to induce iTregs due to defects in both antigen presenting cells and T cells (123.1)

Abstract

Abstract Quantitative and qualitative defects in regulatory T cells (CD4+CD25+Foxp3+; Tregs) are associated with many autoimmune diseases, including systemic lupus erythematosus (SLE). SLE-prone (NZBxNZW)F1 (BWF1) mice have very low frequencies of CD4+Foxp3+ in lymphoid organs compared to non-autoimmune strains, and adoptive transfer of Tregs prevents SLE presumably by restoring the “proper” Treg:effector T cell ratios. In this study, we investigated the mechanisms that could affect Treg frequencies in BWF1 mice. There were no differences in either thymic production or peripheral proliferation of Tregs between BWF1 and control mice. However, in vitro induction of Treg conversion (iTregs) was defective using either BWF1 antigen presenting cells, i.e., TGFβ-treated bone marrow-derived dendritic cells (DC) or untreated CD103+ DC (DC able to induce conversion constitutively), or BWF1 T cells. Furthermore, BWF1 mesenteric lymph nodes contained decreased CD103+ DC concomitant with decreased Helios-CD4+Foxp3+ cells (a potential marker of iTregs) frequencies compared to controls. Taken together, these data suggest that defects in both DC and T cells in BWF1 mice lead to defective conversion of iTregs and may contribute to the decreased Treg frequencies, and consequently, to the development of disease. Identifying the mechanisms that cause these defects could lead to the development of therapeutic strategies that restore an optimal Treg compartment, and thereby treat lupus.