Btn2a2, a member of the butyrophilin family within the immunoglobulin superfamily, is a surface receptor. It is a co-stimulatory molecule first identified on antigen-presenting cells. Btn2a2 plays a crucial role in modulating T cell-mediated immunity, regulating T cell activation, and influencing central T cell tolerance. It is transcriptionally regulated by factors related to major histocompatibility complex class II expression, suggesting its involvement in T cell-related immune pathways [5,6].

In Btn2a2-deficient mice, thymic T cell maturation is altered, and central tolerance mechanisms are bypassed. These mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), with the formation of tertiary lymphoid structures (TLS) in target organs. Absence of Btn2a2 leads to increased TCR signaling and CD5 levels in developing thymocytes [1]. Also, lack of Btn2a2 expression on ILC2 results in elevated T cell responses, enhanced T cell proliferation, and increased secretion of type 2 cytokines. In vivo, Btn2a2-deficient ILC2 induce stronger T cell responses and prevent chronic helminth infections [2]. Moreover, BTN2A2-Ig fusion protein treatment in EAE and CIA mouse models attenuates disease progression. It reduces T cell activation, proliferation, and Th1/Th17 cytokine production, and inhibits the differentiation of pathogenic Th17 cells [3,4].

In conclusion, Btn2a2 is essential for promoting central T cell tolerance by modulating TCR signaling strength. Gene-knockout mouse models have revealed its significant role in autoimmune diseases such as pSS, multiple sclerosis (EAE model), and rheumatoid arthritis (CIA model). These findings provide potential therapeutic targets for treating such autoimmune conditions.

References:

1. Frech, Michael, Danzer, Heike, Uchil, Pooja, Schett, Georg, Zaiss, Mario M. 2023. Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease. In Journal of autoimmunity, 139, 103071. doi:10.1016/j.jaut.2023.103071. https://pubmed.ncbi.nlm.nih.gov/37356345/

2. Frech, Michael, Omata, Yasunori, Schmalzl, Angelika, Zaiss, Mario M, Sarter, Kerstin. 2022. Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses. In Frontiers in immunology, 13, 757436. doi:10.3389/fimmu.2022.757436. https://pubmed.ncbi.nlm.nih.gov/35145516/

3. Huang, Youjiao, Han, Feng, Li, Jiaju, Su, Min, Hu, Rong. 2023. BTN2A2-Ig protein inhibits the differentiation of pathogenic Th17 cells and attenuates EAE in mice. In Immunology letters, 260, 58-67. doi:10.1016/j.imlet.2023.06.009. https://pubmed.ncbi.nlm.nih.gov/37369312/

4. He, Xueping, Hu, Rong, Luo, Peng, Lai, Laijun, Su, Min. 2021. BTN2A2 protein negatively regulates T cells to ameliorate collagen-induced arthritis in mice. In Scientific reports, 11, 19375. doi:10.1038/s41598-021-98443-5. https://pubmed.ncbi.nlm.nih.gov/34588505/

5. Sarter, Kerstin, Leimgruber, Elisa, Gobet, Florian, Hugues, Stéphanie, Reith, Walter. 2016. Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes. In The Journal of experimental medicine, 213, 177-87. doi:10.1084/jem.20150435. https://pubmed.ncbi.nlm.nih.gov/26809444/

6. Brunschwiler, Fabienne, Nakka, Surender, Guerra, Jessica, Guarda, Greta. 2024. A Ménage à trois: NLRC5, immunity, and metabolism. In Frontiers in immunology, 15, 1426620. doi:10.3389/fimmu.2024.1426620. https://pubmed.ncbi.nlm.nih.gov/39035010/