Do human B-1 lymphocytes truly exist?

B-1 cells are a subset of B cells with innate-like properties discovered in the early 1980s in mice. They are important contributors to homeostasis, partly because they secrete natural antibodies with regulatory and scavenging functions. They mainly reside in the pleural and peritoneal cavities, as well as in the spleen and lamina propria of the intestinal mucosa. They differ from conventional (B-2) cells in their ontogeny, phenotype, and functions. In humans, the search for a B-1 cell counterpart began shortly after their discovery in mice, but several difficulties hindered their identification, due to inaccurate phenotypic markers and limited accessibility to the sites where they reside. In this review, we discuss the findings regarding B-1 cells in humans and compare them with murine B-1 cells. In 2011, human B-1-like cells were identified based on functional features and were found to have a CD19⁺ CD20⁺ (or IgM⁺) CD27⁺ CD38^low/int CD43⁺ phenotype. This discovery was vigorously debated, but their existence and equivalence to murine B-1 cells has gained acceptance in recent years. These human B-1 cells are present in blood, skin, pleural and peritoneal cavities, the spleen, and several fetal tissues. They exhibit tonic intracellular signaling and spontaneously secrete antibodies that share certain specificities with classical natural antibodies (e.g., against phosphorylcholine or bacterial polysaccharides). However, they also differ from murine B-1 cells in several aspects, including somatic hypermutation and spontaneous secretion of IgG. Several questions remain unresolved regarding their tissue residency, developmental origin during fetal life, and contribution to immune homeostasis. Moreover, evidence addressing their involvement in infectious, inflammatory, and immune-mediated diseases, remains limited and sometimes controversial, although most studies suggest a protective role. In this review, we critically examine these open questions, highlight areas of consensus and debate, and outline future directions necessary to better define the biology and clinical relevance of human B-1 cells.