Autoantibody production in lpr/lpr gld/gld mice reflects accumulation of CD4+ effector cells that are resistant to regulatory T cell activity

• Published in: Journal of autoimmunity 2008-09, Vol.31 (2), p.98-109
• Main Authors: Hondowicz, Brian D, Fields, Michele L, Nish, Simone A, Larkin, Joseph, III, Caton, Andrew J, Erikson, Jan
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Allergy and Immunology; Animals; Autoantibodies - biosynthesis; Autoantibody; B-Lymphocytes - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Fas/FasL; Female; Forkhead Transcription Factors - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; IFN-γ; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred MRL lpr; Mice, Mutant Strains; T regulatory; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2008.04.022

Abstract In Fas/FasL-deficient mice anti-chromatin Ab production is T cell dependent and is not apparent until after 10 weeks of age. Early control of anti-chromatin antibodies may be due to the counterbalancing influence of Treg cells. Here we show that Treg cells block lpr/lpr gld/gld Th cells from providing help to anti-chromatin B cells in an in vivo transfer system. Interestingly, the percentage and absolute numbers of Foxp3+ Treg cells is elevated in BALB/c- lpr/lpr gld/gld mice and increases with age compared to BALB/c mice. The majority of Foxp3 expression is found in the B220− CD4+ T cell population, and Foxp3-expressing cells are localized in the splenic PALS (periarteriolar lymphocyte sheath). Strikingly, although the lack of functional Fas/FasL does not affect the ability of Treg cells to block Th cell proliferation, Treg cells can block the IFN-γ differentiation of Th cells from BALB/c or young BALB- lpr/lpr gld/gld mice but not of pre-existing Th1 cells from older BALB/c- lpr/lpr gld/gld mice. Thus, we suggest autoantibody production is not caused by the lack of Treg cells but by a defect in activation-induced cell death that leads to the accumulation of T effector cells that are resistant to regulatory T cell activity.