ABSTRACTIn the evolution of the animal kingdom, the first cell to appear that was specialized for a function in host defense was the mononuclear phagocyte. In primitive marine invertebrates such as the starfish and the limpet, freely wandering mononuclear phagocyte cells, the coelomocytes, are the ancestors of the cells of the monocyte/macrophage system found in higher vertebrates and man. As the complexity of higher organisms increased and the specific immune system evolved, the mononuclear phagocyte continued to play a central position in the process of host defense. This report explores the hypothesis that the systems used by the mononuclear phagocyte in primitive invertebrates for recognition of self from nonself have been preserved throughout evolution as part of the foundation of the system of adaptive immunity. Evidence is presented that nonimmune cytotoxic mononuclear phagocytes from invertebrates as well as from man recognize and kill foreign cells using lectin-like receptors which interact with the carbohydrate portion of glycoproteins and glycolipids on the foreign cell surface membrane. Further evidence is presented showing that immune processes such as immunoregulatory interactions involving suppressor T cells and suppressor factors controlling both T cell proliferation and immunoglobulin production by B cells also rely on cellular lectincarbohydrate interactions. We speculate on the basis of these observations that a principal mechanism of cellular recognition, cellular cooperation, and regulation in host defense is based on a fundamental sugar code system involving the interaction of cell surface and secreted lectin-like molecules with carbohydrate polymer receptor structures on the membranes of cells from both self and nonself.