Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling. Essential for trafficking and compartmentalization of CD19 receptor on the cell surface of activated B cells (PubMed:23499492). Upon initial encounter with a microbial pathogen, enables the assembly of CD19-CR2 and B cell receptor complexes at signaling TERMs, lowering the threshold dose of antigen required to trigger B cell clonal expansion and humoral immune response (By similarity). In T cells, associates with CD4 or CD8 coreceptors and defines the maturation state of antigen-induced synapses with B cells (By similarity). Facilitates localization of CD3 in these immune synapses, required for costimulation and sustained activation of T cells, preferentially triggering T helper type 2 immune response (PubMed:11046035). Can act both as positive and negative regulator of homotypic or heterotypic cell-cell fusion processes. In myoblasts, associates with another tetraspanin CD9 in complex with PTGFRN and inhibits myotube fusion during muscle regeneration (PubMed:23575678). In macrophages, associates with CD9 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles. Also prevents the fusion between mononuclear cell progenitors into osteoclasts in charge of bone resorption. Positively regulates sperm-egg fusion and may be involved in the acrosome reaction (PubMed:16380109, PubMed:17290409). Regulates protein trafficking in intracellular compartments. In T cells, associates with dNTPase SAMHD1 and defines its subcellular location, enabling its degradation by the proteasome and thereby controlling intracellular dNTP levels (By similarity). Also regulates integrin-dependent migration of macrophages, particularly relevant for inflammatory response in the lung (PubMed:18662991). (Microbial infection) Specifically required for Plasmodium yoelii infectivity of hepatocytes, controlling sporozoite entry in hepatocytes via the parasitophorous vacuole and subsequent parasite differentiation to exoerythrocytic forms. Homodimer (By similarity). Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B cells. Interacts (via the second extracellular domain) with CD19; this interaction is initiated early during biosynthesis in the ER and enables trafficking of only properly folded CD19 (By similarity). Part of a complex that includes MHC class II/HLA-DR molecules and IFITM1. Interacts with IFITM1 (By similarity). Interacts with IFITM2 and IFITM3 (PubMed:16395393). Part of integrin-tetraspanin complex composed of CD9, CD81, beta-1 and beta-2 integrins in the membrane of monocyte/macrophages (By similarity). Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3 (By similarity). Interacts with CD247/CD3 zeta, ICAM1 and CD9 at the immune synapse on T cell membrane (By similarity). Part of a GPCR-tetraspanin complex consisting at least of ADGRG1, CD81, possibly CD9, and GNA11 in which CD81 enhances the association of ADGRG1 with GNA11 (By similarity). Part of a complex composed of CD9, CD81, PTGFRN and IGSF8 (PubMed:23575678). Interacts directly with IGSF8 (PubMed:11673522). Interacts with CD53 and SCIMP (By similarity). Interacts with SAMHD1 (via its C-terminus) (By similarity). Interacts with glypican GPC3 and with the transcriptional repressor HHEX; binding to GPC3 decreases the availability of free CD81 for binding to HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (PubMed:23665349). Interacts with CLDN1 (By similarity). Interacts with CLDN6 and CLDN9 (By similarity). Associates with CLDN1 and the CLDN1-CD81 complex localizes to the basolateral cell membrane. Expressed in oocytes (at protein level) (PubMed:16380109, PubMed:17290409, PubMed:23213457). Highly expressed in granulosa cells (PubMed:16380109). Expressed in skeletal muscle mainly in endothelial cells of endomysial capillaries, in satellite cells and myoblasts (at protein level) (PubMed:23575678). Expressed in hepatocytes (at protein level) (PubMed:12483205). Up-regulated in response to notexin-induced acute myoinjury. Binds cholesterol in a cavity lined by the transmembrane spans. Not glycosylated. Likely constitutively palmitoylated at low levels. Protein palmitoylation is up-regulated upon coligation of BCR and CD9-C2R-CD81 complexes in lipid rafts. Knockout mice exhibit reduced female fertitily and impaired egg-sperm fusion (PubMed:16380109, PubMed:17290409). In response to notexin-induced acute myoinjury, mutant mice display abnormal muscle regeneration characterized by typical giant distrophic myofibres (PubMed:23575678). Mutant mice show reduced allergen-induced lung inflammation, eosinophilia and mucin production (PubMed:11046035). These mice spontaneously develop multinucleated giant cells (MGCs) and show enhanced osteoclastogenesis when compared to wild-type littermates (PubMed:12796480). CD81 and CD9 double knockout mice develop pulmonary emphysema, reminiscent of chronic obstructive pulmonary disease in human (PubMed:18662991). (Microbial infection) Mutant mice are refractory to Plasmodium yoelii sporozoite infection. Belongs to the tetraspanin (TM4SF) family.