Biochemical analysis of the TCR/CD3 complex (G?bel et al., 2000) and characterization of TCR genes in (Chrtien et al., 1997) also revealed features that are similar to mammals. ancient origin (bony and cartilaginous fishes), that shared a common ancestor ~350 MYA (Pough et al., 2002). In addition to its wide use for developmental studies, has been, and still is frequently used as the nonmammalian comparative model of choice for immunological studies. Indeed, provides a versatile model with which to study ontogeny and phylogeny of humoral and cell-mediated immunity against tumors and pathogens. Features such as the accessibility of early developmental stages free of maternal influence to manipulation and surgery, the transparency of tadpoles, the developmental transition from larva to adult during metamorphosis; and the direct effect of temperature on immune responses and are all attractive and useful for fundamental studies of the ontogeny of the immune system. Vertebrate immune systems are classically categorized into two interconnected types: innate and adaptive immune systems. Innate immunity provides a first line of defense using a wide variety of cells and pathways that target pathogens globally. Effector cells of innate immunity (i.e., macrophages, neutrophils, dendritic cells, and natural killer [NK] cells) eliminate infected cells by phagocytosis or by direct cytotoxicity. Activation of innate immune responses in vertebrates occurs through the interaction of pattern recognition receptors (PRRs) on effector cells with molecules specific to pathogens (pathogen-associated molecular patterns [PAMPs]). The PRRs are germline-encoded and their recognition is necessarily limited (i.e., broad specificity). Engagement of PAMPs by the PRRs initiates biochemical cascades that stimulate effector cells and that induce the release of soluble Methazolastone mediators reacting against different types of pathogens. Innate immunity also includes antimicrobial peptides that are secreted onto the skin, as well as serum proteins (including acute phase proteins) and complement components that are secreted by the liver. Innate immune systems in vertebrates also play a crucial role in initiating adaptive immune responses that are specific to the foreign antigen (reviewed in Janeway, 1992). The adaptive immune system of vertebrates (defined in details in section 1.2) is characterized by B and T cells Methazolastone expressing surface Ag-specific Methazolastone receptors, which in contrast to germline-encoded innate PRRs, are somatically generated by recombination-activating genes (RAG)-dependent gene rearrangements. These Ag receptors are incredibly diverse in each individual and can recognize Ags that differ even subtly from self at the molecular level. Thus, it is often referred to as an anticipatory system because it (theoretically) can be stimulated by any non-self molecule. The vertebrate adaptive immune system is evolutionarily more recent than innate immune systems. It mysteriously appeared as a whole near the time of the emergence of jawed vertebrates ~500 million years ago (MYA; reviewed in Flajnik and Kasahara, 2001). In jawless fish (e.g., lamprey, hagfish) and some invertebrates (e.g., fruit fly), other types of adaptive somatic diversification have arisen as well, apparently by convergence (Pancer et al., 2004, 2005; Watson et al., 2005). To date, remains one of the most comprehensively studied ectothermic vertebrates with respect to its adaptive immune system (reviewed in Du Pasquier et al., 1989), which in adults, is remarkably similar to that of mammals. Importantly, is a transitional animal model, being the oldest vertebrate INTS6 class in which the immunoglobulin (Ig) class switch occurs, but does so in the absence of germinal center formation critical for T cell-dependent B-cell maturation in mammals (Marr et al., 2007; reviewed in Du Pasquier et al., 2000; and Flajnik, 2002). Most of the cell types of hematopoietic origin as defined in mammals are present in over several decades have resulted in the generation of many invaluable research tools, including MHC-defined clones and inbred strains Methazolastone of animals, transplantable lymphoid tumor cell lines, monoclonal antibodies (mAbs), and cDNA probes (http://www.urmc.rochester.edu/smd/mbi/xenopus/index.htm). Recently, rather than the allotetraploid species, (reviewed.