Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease

• DOI: 10.1016/j.jaut.2023.103071
• Publication Date: 2023-06-24T19:35:45Z
• Authors: Michael Frech; Heike Danzer; Pooja Uchil; Vugar Azizov; Eva Schmid; Fabian Schälter; Kerstin Dürholz; Daniele Mauro; Simon Rauber; Luis Muñoz; Leila Taher; Francesco Ciccia; Kilian Schober; Magali Irla; Kerstin Sarter; Georg Schett; Mario M. Zaiss
• Keywords: Thymic epithelial cells (TEC); Primary sjogren's syndrome (pSS); Butyrophilins; Central tolerance; Autoimmune disease; Autoimmunity; Butyrophilin 2a2 (Btn2a2); Central tolerance; Primary sjögren's syndrome (pSS); Thymic epithelial cells (TEC); Receptors, Antigen, T-Cell; Autoimmunity; Epithelial Cells; Thymus Gland; Butyrophilin 2a2 (Btn2a2); Autoimmune Diseases; Mice; [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology; Autoimmune disease; Central Tolerance; [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Humans; Animals

Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2-/- mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.