CD5 is a lymphoid-specific receptor expressed by all T cells and a subset of B cells (B1a cells) that functions as a critical regulator of immune homeostasis and T cell immunity. Primary function: CD5 acts as a negative regulator of T cell receptor (TCR) and B cell receptor (BCR) signaling during thymocyte development and peripheral T cell maturation 1. Mechanism: CD5 operates through two distinct pathways—in T cells, it associates with signaling proteins including LCK and CBL, modulating TCR signal strength as read by surface CD5 expression levels 1; in B cells, CD5 modulates biology through ERK1/2 activation via the calcium channel TRPC1, promoting IL-10 production. CD5 also mediates T-dependent B cell activation through interactions with ligands such as CD5L and CD72. Disease relevance: CD5+ B cells are expanded in autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus, and malignant expression characterizes chr11 B cell lymphoproliferative disorders 2. Clinical significance: CD5 expression on dendritic cells correlates with melanoma patient survival and is essential for optimal anti-tumor immunity and checkpoint blockade therapy responses 3. CD5 surface levels serve as a biomarker for identifying functionally heterogeneous T cell populations with implications for adoptive cell therapies 1.