CD161 is a C-type lectin-like receptor and a type II transmembrane protein, widely expressed on various lymphocytes, including natural killer (NK) cells, CD4+ T cells, CD8+ T cells, and mucosal-associated invariant T (MAIT) cells. It functions as a co-stimulatory molecule, influencing T cell receptor (TCR)-dependent responses. CD161+ T cells are enriched in the gut and exhibit enhanced cytokine production. However, the exact mechanisms of CD161 are still controversial, as it may have both promoting and inhibitory roles in T cell activation. Additionally, CD161 is associated with transcriptional and functional phenotypes across different T cell lineages, with some conserved features among these subsets.