Foxp3+ regulatory T cells control humoral autoimmunity by suppressing the development of long-lived plasma cells

• Published in: The Journal of immunology (1950) 2011-02, Vol.186 (3), p.1546-1553
• Main Authors: Jang, Eunkyeong, Cho, Wang Sik, Cho, Mi-La, Park, Hyun-Joo, Oh, Hye-Joa, Kang, Sang Mee, Paik, Doo-Jin, Youn, Jeehee
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Autoantibodies - biosynthesis; Autoantibodies - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Survival - genetics; Cell Survival - immunology; Cells, Cultured; Coculture Techniques; Down-Regulation - genetics; Down-Regulation - immunology; Female; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; Growth Inhibitors - biosynthesis; Growth Inhibitors - genetics; Growth Inhibitors - physiology; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymph Nodes - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Plasma Cells - immunology; Plasma Cells - metabolism; Plasma Cells - pathology; Spleen - immunology; Spleen - metabolism; Spleen - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002942

Foxp3(+) regulatory T cells (Tregs) are crucial for maintaining T cell tolerance, but their role in humoral autoimmunity remains unclear. To address this, we combined a model of autoantibody-dependent arthritis (K/BxN) with Foxp3 mutant scurfy mice to generate Treg-deficient K/BxN mice, referred to as K/BxNsf mice. The disease symptoms of K/BxNsf mice were exacerbated, and this coincided with increases in extrafollicular Th cells, follicular Th cells, and germinal centers. Surprisingly, the K/BxNsf mice exhibited an abnormal accumulation of mature plasma cells in their spleens and a corresponding loss of bone marrow plasma cells. The plasma cells were unresponsive to the bone marrow homing chemokine CXCL12, despite normal expression of the chemokine receptor CXCR4. Importantly, they were long-lived and less susceptible to the cytotoxic action of cyclophosphamide. They also expressed less FcγRIIb and were less apoptotic in response to autoantigen-autoantibody immune complexes. This suggests that Tregs control plasma cell susceptibility to cell death induced by engagement of FcγRIIb with immune complexes. Direct cytotoxic effects of Tregs also contribute to the death of plasma cells. Thus, our results reveal that Tregs suppress the emergence of long-lived splenic plasma cells by affecting plasma cell-autonomous mechanisms as well as T cell help, thereby avoiding the persistence of humoral autoimmunity.