N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis

• Published in: Molecular immunology 2024-02, Vol.166, p.39-49
• Main Authors: Hansda, Anita, Goswami, Saumyadeep, Mukherjee, Sarbartha, Basak, Aditya J., Dasgupta, Shirin, Roy, Pritam Kumar, Samanta, Dibyendu, Mukherjee, Gayatri
• Format: Article
• Language: English
• Subjects: Animals; BTNL2; Butyrophilins - metabolism; CD8-Positive T-Lymphocytes; Colitis; Colitis, Ulcerative - chemically induced; N-terminal IgV domain; Peyer's Patches - metabolism; Peyer’s Patches; T cell inhibition; Ulcerative colitis
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2024.01.004

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer’s patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer’s patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer’s patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1. •N-terminal ectodomain of BTNL2 (BTNL2 IgV1) alone can inhibit T cell function.•BTNL2 IgV1 uses a non-canonical binding interface with its putative receptor.•T cells expressing BTNL2 receptor in Peyer’s Patch participate in colitis pathogenesis.•Exogenous administration of BTNL2 IgV1 delays ulcerative colitis progression.•BTNL2 IgV1 delays colitis progression by inhibiting T cells expressing BTNL2 receptor.