BTNL2 is a negative regulator of T-cell proliferation that functions as an immune checkpoint molecule within the B7:CD28 family 1. Located on the external side of the plasma membrane, BTNL2 engages with multiple immune cell populations including γδ T cells, CD4+ T cells, and group 3 innate lymphoid cells to modulate immune responses 23. Mechanistically, BTNL2 promotes IL-22 and IL-17A production through interactions with these lymphocyte subsets, thereby suppressing anti-tumor immunity and maintaining immune tolerance 23. Clinically, BTNL2 is strongly associated with sarcoidosis susceptibility. The rs2076530 polymorphism significantly increases sarcoidosis risk across multiple genetic models (OR=1.59-2.10) 4, with the 6p21 genomic region containing BTNL2 identified as a major locus for genetic predisposition 56. This polymorphism also influences sarcoid uveitis presentation in specific patient subgroups 7. Therapeutically, BTNL2 blockade shows promise as an immunotherapy strategy. Monoclonal antibodies against BTNL2 attenuate colorectal tumorigenesis and ameliorate colitis in preclinical models 2, while reducing tumor-infiltrating immunosuppressive cells and promoting anti-tumor immunity 3. High BTNL2 expression in human tumors correlates with poor survival outcomes, suggesting dual therapeutic potential in both cancer and inflammatory diseases.