Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Foxp3 CD4 Tregs Prevent Arthritis by Promoting Clonal Anergy Induction in Self Ag-Specific CD4 T Cells.
Martinez2, Ryan, Zhang2, Na, Nandiwada2, Sara, Thomas2, Stephanie, Binstadt2, Bryce, Mueller1, Daniel L.
Using a mouse model of self Ag recognition by naive CD4+ T cells, we have investigated the peripheral self tolerance mechanism that prevents the development of autoimmune arthritis in most individuals. As previously reported, an adoptive transfer of glucose 6-phosphate isomerase (GPI)-specific naive KRN TCR-transgenic CD4+ T cells into lymphopenic TCRalpha chain-deficient mice that naturally express GPI/I-Ag7 complexes led to an intense clonal expansion, the production of anti-GPI IgG1 autoantibody, and the development of severe polyarticular arthritis. Recognition of GPI/I-Ag7 in normal hosts, however, failed to elicit autoimmune disease, and instead was sufficient to stimulate only an abortive KRN CD4+ T cell clonal expansion and the induction of clonal anergy. Anergic KRN CD4+ T cells demonstrated a reduced proliferative responsiveness to Ag stimulation, the inhibition of IL-2, TNF-alpha, and IFN-gamma synthesis, and high-level expression of CD73 and Folate receptor 4 (FR4). Reconstitution of the T cell-deficient hosts with enriched CD25+ Foxp3+ CD4+ T cells was sufficient to promote the induction of KRN T cell clonal anergy and prevent the development of arthritis. More importantly, use of diphtheria toxin to selectively eliminate Foxp3-expressing cells from T cell-deficient hosts that had been reconstituted with polyclonal CD4+ T cells from Foxp3-GFP-diphtheria toxin receptor transgenic mice, prevented the development of clonal anergy in the transferred naive KRN CD4+ T cells, and led to their induction of autoimmune arthritis. These data suggest that during the initial encounter of naive CD4+ T cells with peripheral self Ag, CD25+ Foxp3+ T regulatory cells ensure that clonal anergy will be induced early during clonal expansion, and autoimmune arthritis can be avoided. Individuals deficient in Foxp3+ T regulatory cell activity or number are prone to autoimmune arthritis as a consequence of exuberant self Ag-specific CD4+ T cell clonal expansion and differentiation, and the provision of pathological helper activity that leads to a breakdown of self tolerance in the B cell compartment.
To cite this abstract, please use the following information:
Martinez, Ryan, Zhang, Na, Nandiwada, Sara, Thomas, Stephanie, Binstadt, Bryce, Mueller, Daniel L.; Foxp3 CD4 Tregs Prevent Arthritis by Promoting Clonal Anergy Induction in Self Ag-Specific CD4 T Cells. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1256