Evolutionary implications of a third lymphocyte lineage in lampreys

Abstract

Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems1,2. Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily3,4. Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells5–7. Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors8,9. Both VLRC+ and VLRA+ lymphocytes express orthologues of genes that gnathostome γδ and αβ T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the ‘thymoid’ gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system.

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…The tripartite subdivision of lymphocytes possessing rearranged receptors into B cells, αβ T cells, and γδ T cells has been conserved since the emergence of jawed vertebrates more than 450 Mya (1). Recently, a similar division of variable lymphocyte receptor A (VLRA) + , VLRB + , and VLRC + cells, resembling αβ T cells, B cells, and γδ T cells, respectively, has been found in jawless vertebrates (e.g., lamprey), showing the same basic principle of lymphocyte differentiation along two distinct T-cell-like lineages and one B-cell-like lineage (4). These evolutionary data highlight the importance of both γδ T cells and αβ T cells.…”

“…Based on the ligands that have been identified, it appears that some γδ TCRs can recognize antigens in an antibody-like fashion, whereas the TCRs of other γδ T-cell subsets can bind to nonclassical MHC-I or MHClike proteins (2,(5)(6)(7)(8)(9)(10)(11). Although there are common characteristics among γδ T cells, some of which are shared with VLRC + cells (4), it is clear that γδ T cells do not represent a homogenous population of cells with a single physiological role (12). γδ T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are activated by microbe-and host-derived phosphorylated prenyl metabolites (phosphorylated antigens or "phosphoantigens") derived from the isoprenoid metabolic pathway, the most active of which are microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, and host isopentenyl pyrophosphate (IPP) (13).…”

Definition of a thirdVLRgene in hagfish

“…In some ways the lamprey VLRA-and VLRC-expressing cells resemble the αβ and γδ T cells of jawed vertebrates, whereas the VLRB-bearing cells are more morphologically and functionally similar to B cells (12,14,16). Hagfish VLRC ("VLRA" in the old nomenclature) and VLRB are also expressed by two distinct lymphocyte populations (26), and the hagfish VLRB protein is secreted (27).…”

“…VLRA-and VLRC-bearing cells also proliferate in response to antigen stimulation, but do not differentiate into antibody secreting cells; instead they maintain cell surface expression of their receptors, while increasing the expression of proinflammatory cytokines, macrophage migration inhibitory factor (MIF), and interleukin-17 (IL-17) (12). CDA1-expressing progenitors assemble their VLRA and VLRC genes to become VLRA + and VLRC + lymphocytes in a thymus-equivalent region of the gills termed the thymoid (15,16). Conversely, VLRB assembly coincides with CDA2 expression during VLRB + lymphocyte development in hematopoietic tissues (15).…”

Selection of the lamprey VLRC antigen receptor repertoire

“…Despite these differences, the immune systems of both jawed and jawless vertebrates possess similar characteristics. For instance, recent work has indicated that lampreys have three distinct lymphocyte lineages, one of B-like cells, and two of T-like cells, and that each lymphocyte lineage of lamprey expresses a distinct type of VLRs, designated VLRA, VLRB, and VLRC, respectively (6). Hagfishes, the second clade of jawless vertebrates, also possess genes encoding orthologs of these three VLR isotypes (7,8), suggesting that distinct lymphocyte lineages and specialized antigen receptor types were integral components of the immune system of the common ancestor of jawless vertebrates.…”