Figure 3.

A simplified phylogenetic tree of TFs and cytokines directing lymphoid effector subset development and function. Depicted are the major phyla (ovals); the kingdoms they belong to (double ovals) and subphyla, classes, or genera they include (bold, referred to in the text); and extant organisms (species) of Opisthokonta (domain Eukaryota, animals and fungi supergroup, no taxonomic rank). Only the holozoan (animals and related unicellular organisms) branch that generated animals (metazoans) is detailed, and the tree is drawn not to a timescale but according to the sequence in which the phyla emerged. Only the clear-cut orthologs of rodent TFs and cytokines (rectangles) are noted in species where they first appear, and for early genes that are not clearly defined as homologs (because a member is missing key functional domains, for instance), they are denoted as ancestral and preceded by the letter a. Lymphocytes only exist in deuterostomes, but it is clear that immune mechanisms, such as the complement cascades and pathogen-associated molecular patterns, predate the emergence of mobile cell types mediating immune responses. Filastereans (Capsaspora owczarzaki), single-cell eukaryotes, and the earliest clade of the holozoan branch are already endowed with intracellular mediators of innate sensors, such as NF-κB, the STAT TF that is activated by cytokine and growth factor receptors; and an ancestral Runx gene linked to the mammalian Runx1, which is essential for definitive hematopoiesis. The closest extant unicellular relatives of animals are choanoflagellates, and they provide evidence for the emergence of sequence-specific HMG TFs, related to Capicua (Cic) and SoxF/H members (Sox17, 18, or 30), ~900 Mya. A significant expansion of the repertoire of immune-related TFs is observed in Porifera (sponges), and a large family of invertebrate IL-17 is found in oysters (Protostomia). A Tbr gene is annotated in the genome of Lottia gigantea, a protostome mollusk, but not in the genome of flies. An ancestral gene for Rag is present in Nematostella vectensis (sea anemone) and further innovated in Strongylocentrotus purpuratus (purple sea urchin), where orthologs of Rag1/2 emerged. Definitive evidence for a discrete ILE subset is first obtained in lampreys, where Il17-expressing SOX13⁺ lymphocytes that home to mucosal tissues have been discovered. The diversification of mammalian cytokines and central antigen receptor–activated TFs controlling αβT cell effector lineage specification initiates in vertebrates, first in cartilaginous fishes (Callorhinchus milii). The emergence of type 2 cytokines appears to lag behind the emergence of type 1 cytokines, as a single Il4/13 gene and an Il5 homolog are catalogued in teleosts, with only an ancestral Il4 gene in C. milii. Among the central modulators of Th cell specification, the mammalian inducers of type 3 cytokines RORγt and IL-23 appear last in teleosts. Abbreviations: HMG, high-mobility group; ILE, innate lymphoid effector; TF, transcription factor.