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• W2079672640 abstract "The discovery of a novel form of antigen receptor in the sea lamprey a few years ago1 signaled a turning point in comparative immunology and perhaps immunology in general. Before this the jawed vertebrates held the high ground of immune sophistication with their elaborate adaptive immune system. The variable lymphocyte receptors (VLR) identified in the jawless vertebrates, the hagfish and lamprey, provide an alternative adaptive immune system for study and thus the opportunity to generalize about somatic diversity. Now, a new twist has been provided in a recent report in Nature that focuses not so much on the VLRs per se but on the remarkable features of the cells that bear them.2 This article reveals two forms of lymphocyte-like cells in the lamprey that each express a distinct VLR locus and share fundamental properties with the B and T cells that populate the adaptive immune system of jawed vertebrates. Rearranged immunoglobulin and T-cell receptors are present in all jawed vertebrates from sharks to humans.3 Years of intense searching in jawless vertebrates and invertebrates for counterparts of these loci failed to turn up rearranging homologs, and emerging genome sequences confirmed their absence. There are candidates for other forms of somatic diversification in invertebrates, but as yet their precise immune functions remain to be defined. The exclusive position of jawed vertebrates in the realm of adaptive immunity disappeared with the discovery of VLRs.1 The VLRs are leucine-rich repeat proteins that are structurally unrelated to the jawed vertebrate immunoglobulin-like domain-based antibodies and T-cell receptors. The agnathan VLR system was identified by careful scrutiny of a diverse family of sequences chosen from a lamprey lymphocyte-like EST project that revealed discrepancies with corresponding genomic sequence. Since the initial description, information has continued to roll out in a series of high-profile papers, each contributing a new piece of the puzzle. In the lamprey, VLR proteins are expressed on cells that resemble lymphocytes in terms of morphology and gene expression, although the significance of these similarities as flags of true homology is still not clear. VLRs are expressed on the cell surface as GPI-linked proteins and also secreted in multimeric forms.4 Two versions of VLRs (VLRA and VLRB) were identified first in the hagfish,5 the only other extant line of jawless fishes, and later shown to be present also in the lamprey.6 Most cells of the lamprey carry unassembled versions of the two VLR subtypes but the lymphocyte-like cells carry versions that have been reconstructed at the genomic level by a gene conversion6 or a copy-choice process.7 The process of VLR assembly is correlated with the expression of a deaminase with distant similarity to the activation induced cytidine deaminase (AICDA)/APOBEC genes.6 Until now, the VLRB subtype has been most thoroughly studied. Specificity has been shown for a number of antigens4, 8 and a structure has been determined for VLRB bound to the H-antigen trisaccharide from human erythrocytes.9 Thus the question arises, why are there two VLR loci? Their conservation over the very long period since the separation of the lamprey and hagfish lineages suggests a fundamental and distinct function for each. A breakthrough to this question came with the production of a panel of monoclonal and polyclonal antibodies to the lamprey VLRA subtype, which, along with an existing panel of VLRB-specific antibodies, were used to isolate cells and follow expression of the receptor proteins.2 Analyses with these reagents immediately revealed dramatic expression differences between these two loci. First, flow cytometric analysis showed that expression of VLRA and VLRB was mutually exclusive. Second, a secreted form of VLRA could not be detected in serum of challenged or unchallenged animals. Furthermore, whereas the VLRB form is secreted in mammalian cell expression systems, the VLRA form can only be detected at the cell surface. This is immediately reminiscent of two arms of the jawed vertebrate system (a fact which Max Cooper had a primary role in showing some 45 years ago10). Guo et al.2 then show that each cell type reorganizes and transcribes only the VLR type that is expressed on its surface. Analyses of genomic organization in VLRA+ cells is consistent with allelic exclusion as had been shown for VLRB+ cells.1 Proliferative responses to specific antigen and the T-cell mitogen phytohemagglutinin differ between the VLRA and VLRB cells in a manner similar to T and B cells of the jawed vertebrate system. These findings are summarized in Figure 1. The authors then quantified the expression of a set of immune homologs in each cell type and found a notable similarity to the distribution of genes expressed by jawed vertebrate T and B lymphocytes. Each of these genes is expressed in a wider array of blood cells and there are some issues as to subfamily orthology that need to be resolved. All of this will come with further investigation but two strong conclusions can be drawn from the gene expression data as it stands. First, similar to the T and B cells of the jawed vertebrate adaptive immune system, the VLRA and VLRB cells are fundamentally different from each other in terms of the genes that they express. Second, some cytokine/chemokine receptor/ligand pairs are expressed in a complementary pattern between the VLRA and VLRB cells. This suggests that the cells may converse with each other, a property that would be prerequisite to behavior that parallels B and T cell interactions in jawed vertebrate immune regulation. The authors state the notable possibility here that the cell-bound VLRA may serve as a regulatory check on the VLRB cells to suppress anti-self specificities. At present it is difficult to interpret the VLR cells as direct evolutionary counterparts of the jawed vertebrate T and B cells. The receptors are unrelated and the expression similarities, while certainly exciting, do not unambiguously ally the VLR cells with lymphocytes or their subtypes. Understanding the relationship among these immune cells speaks to a central issue in evolutionary biology: the nature of homology in relation to cell types. Detailed analysis of the regulatory networks that control the VLR system will lend the type of specific information needed for a solution to this problem. For now it is safest to treat the VLR and immunoglobulin/T-cell receptor systems as convergent, which, even if so, in no way lessens the impact of the finding. The most important product of this work may ultimately be an understanding that transcends the particulars of shared inheritance and settles on the fundamental constraints that guide the evolution and regulation of adaptive immunity. Functional parallels between antigen recognition systems in jawless and jawed vertebrates. Columns contain characters from a representative jawless vertebrate (lamprey) and jawed vertebrate (mouse). In each, somatic mechanisms diversify the receptors. Each diversification event is clonal and for the most part monoallelic in both systems. Differential responses to antigen are segregated into two major cell types in both jawless and jawed vertebrates. VLRA-expressing cells, like T cells, proliferate in response to antigen but do not secrete soluble antibodies, whereas VLRB cells, like B cells, not only proliferate but also produce soluble antibodies. Both VLR and Ig antibodies can exist as multimers. Reciprocal cell–cell communication occurs between B cells and T cells and is an important component of the mechanisms that supresses an anti-self immune response. Emerging evidence suggests this possibility for VLRA and VLRB as well." @default.
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• W2079672640 date "2009-08-11" @default.
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• W2079672640 title "Universal rules of immunity" @default.
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• W2079672640 doi "https://doi.org/10.1038/icb.2009.54" @default.
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