Analysis of Treg defects in female (NZBxNZW)F1 mice with established disease (48.21)

Abstract

(NZBxNZW)F1 (BWF1) is a mouse model of SLE in which females develop nephritis by 36 wks. Sick female BWF1 mice have considerably more Foxp3+ Tregs than age-matched non-sick females and males, but these Tregs are unable to control disease. BrdU uptake by CD4+ (non-Treg) cells was increased in sick female mice, suggesting that CD4 activation/proliferation was not well-controlled in vivo in these mice. However, in in vitro analyses of cells from sick females, no defects in Treg function, responder cell sensitivity to suppression or APC activation of Tregs were detected. CD103+ Tregs, a memory/effector subset, were also increased in sick mice. Vβ TCR usage by CD103+ Tregs differed between sick and non-sick mice suggesting the Treg TCR repertoire, and possibly the antigen specificity of Tregs, could be altered in sick mice. Expression of molecules that affect lymphocyte trafficking was also analyzed. In sick mice, no increases in E-cadherin, the CD103 ligand expressed by activated B cells and epithelium, or other molecules associated with lymphocyte sequestration (e.g., CD62L) in lymphoid organs were detected. However, CXCR3, which is involved in trafficking to inflamed sites, was decreased in CD103+ Tregs from sick mice. These data suggest that features of Tregs other than their inherent regulatory function could be altered in sick mice; however, it is unclear whether this is a cause or an effect of inflammation. Funded by LRI.