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Keywords:

  • adaptive immunity;
  • innate immunity;
  • T and B cells;
  • variable lymphocyte receptors

Summary

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

Adaptive immunity has been defined, principally through studies of avian and mammalian species, as the ability to mount specific immune responses to a virtually unlimited variety of antigens. A key feature of an adaptive immune system is the ability to remember previous encounters with antigens and to achieve a more rapid, heightened response on secondary encounter. Adaptive immune systems featuring an enormous anticipatory receptor diversity and specific memory have been defined only in vertebrates. Surprisingly, the adaptive immune systems in jawless and jawed vertebrates employ very different types of antigen receptors. This evolutionary inventiveness suggests that adaptive immunity provided additional fitness value over the previously existing innate immune mechanisms.


Adaptive immunity in jawed vertebrates

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

The adaptive immune system in all of the jawed vertebrates is featured by antigen-specific cellular and humoral immunity, which together provide durable protective immunity against microbial infections [1]. This division of labour is conducted by developmentally separate, but functionally interactive populations of clonally diverse lymphocytes. These are named T and B cells because their haematopoietic progenitors begin their lymphocyte differentiation, respectively, in the thymus and in the avian bursa of Fabricius or mammalian bone marrow [1,2]. Both lymphocyte populations employ immunoglobulin (Ig)-based receptors for antigen recognition. The T cell receptors (TCR) and B cell receptors (BCR) are assembled during lymphocyte differentiation by the recombination of different variable (V), diversity (D) and joining (J) gene segments, imprecise V(D)J splicing and insertion of non-templated nucleotides at the junctions [3,4]. This assembly process, which is initiated by the recombinase activating genes 1 and 2, is usually completed on one allele only. The monoallelic gene assembly results in the expression of a different antigen recognition receptor on each T and B cell. Clonal diversity of the T and B lymphocyte populations, which have both recognition and effector functions, is a central feature of the adaptive immune system in jawed vertebrates.

The antigen-binding repertoires of T and B cells are very different, despite the fact that the TCR and BCR genes are very similar. This difference is attributable primarily to the clonal selection that immature T cells undergo in the thymus [5]. The selection for T cell survival or death depends upon how well the TCR recognizes major histocompatibility complex (MHC) class I or class II molecules and their self-peptide cargos. This intrathymic repertoire selection serves as a central mechanism to eliminate T cells that can recognize and potentially damage self-tissues. After their exit from the thymus the mature T and B cells work together to achieve effective cellular and humoral immunity. This collaboration involves both direct cell contact and indirect communication via cytokines and their receptors [1].

T and B lymphocytes are highly mobile cells that circulate via the interconnecting vascular and lymphatic channels throughout the body. During the course of their chemokine/chemokine receptor-guided migration to protect against potential microbial pathogens, T and B cell responses are co-ordinated in strategically located secondary lymphoid tissues. These co-ordination centres include the spleen, lymph nodes, intestinal Peyer's patches and appendix in mammals. Adaptive immune responses are initiated and orchestrated by the T cells, which may follow one of several specialized differentiation pathways [6]. One of the initial fate-determining decisions of a thymocyte progenitor on reaching the thymus is whether to begin the assembly of a γδ or αβTCR gene. The functions of the γδ T cells are not well understood, but it seems likely that they function in co-ordination with the αβ T cells, as the γδ and αβ T cells are interactive [7], conserved in all jawed vertebrates and found together typically in antigen-induced T cell responses. The numerically dominant T cells undergo further diversification by differential maturation to become CD4+ T helper type 1 cells (Th1, inflammatory T cells), Th2 cells (helpers of B cell responses), follicular T helper cells (TFH, helper T cells in germinal centres), Th17 cells [producers of the interleukin (IL-17) proinflammatory cytokine], CD8+ cytotoxic T cells, natural killer T cells (NK T, oligoclonal producers of multiple cytokines) or regulatory T cells (Tregs, down-regulators of T cell responses). Complex interactions between these different T cell subsets serve to balance cellular and humoral responses both for defence purposes and to safeguard against harmful autoimmune reactions. The B cells also undergo subset diversification to serve functions other than antibody production. One of the most prominent of the auxiliary B cell functions is to present MHC-II bound antigen fragments together with cell surface co-stimulatory molecules to activate CD4+ helper T cells, the function of which is essential for the initiation of most specific immune responses.

Clonally diverse T and B cells collaborate with a diverse cast of cellular and molecular elements of the innate immune system. Dendritic cells are specialized to process and present antigens to activate T cells in order to initiate the adaptive immune response [8]. NK lymphocytes use a diverse set of non-somatically diversified, but differentially expressed receptors to recognize pathogen-associated molecular patterns and to respond quickly to pathogen invaders for defence purposes [9]. Monocyte/macrophage lineage cells can present antigens to T cells and they also participate actively in protective inflammatory responses [10]. They do this in concert with other types of phagocytic cells and a wide array of humoral components that contribute to innate immunity.

The cardinal elements of the Ig-based adaptive immune system [recombinase-activating gene (RAG)1/2, BCR, TCR and MHC-I/II] are shared by all jawed vertebrates [1,11]. Even the cartilaginous fish (sharks, skates and rays) have B cells that express Ig heavy and light chain genes, a thymus, T cells that express TCR α, β, γ and δ genes and MHC class I and class II genes. Secondary lymphoid organs are not well developed in the more basal jawed vertebrates, however. Phylogenetic studies of dendritic cells and NK cells are limited, although both are presumed to be present in all jawed vertebrates. When and how the Ig-based adaptive immune system evolved is also still speculative. An important reason for this uncertainty is that the most basal jawed vertebrates, such as the dermal armoured fishes, are known only through their fossil remains, which were deposited around 360 million years ago [12].

Adaptive immunity in jawless vertebrates

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

The two living representatives of the jawless vertebrates, lamprey and hagfish, have not been found to have a recognizable thymus, and they lack the TCR, BCR and MHC elements of our adaptive immune system [13,14]. Nevertheless, these relatively long-lived animals were found to have lymphocyte-like cells and to produce antigen-specific agglutinins in response to immunization with bacteria and heterologous erythrocytes [15]. Recent studies indicate that these agnathans have an adaptive immune system that employs a different kind of antigen-recognition molecule [16,17]. Lampreys and hagfish generate clonally diverse lymphocytes through the somatic assembly of genes for variable lymphocyte receptors (VLR) that serve as counterparts to our Ig-based TCR and BCR for antigens [17,18]. VLRs are comprised of variable leucine-rich-repeat (LRR) subunits and a membrane-proximal stalk region. The two germline VLR genes are incomplete, in that they contain coding sequences only for a leader sequence, limited portions of the N-terminal and C-terminal LRR subunits, which are separated by intervening non-coding sequences, and the invariant stalk region. Each of the VLR genes is flanked by hundreds of LRR coding sequences that can be used as templates to add the missing LRR segments needed to construct a mature VLR gene. The donor LRR sequences are thought to be anchored temporarily to a recipient 5′ LRR or 3′ LRR sequence via short stretches of nucleotide sequence homology and then the additional donor sequence is copied to extend the recipient sequence [19,20,21]. This type of LRR sequence extension is repeated until the VLR gene under construction is completed. The VLR assembly process is limited to one VLR allele, thus assuring the expression of a unique VLR by individual lymphocytes and clonal diversity of the population. The mechanism for VLR assembly is postulated to involve a special type of gene conversion. Two AID-APOBEC cytidine deaminase family members, CDA1 and CDA2, in the lamprey resemble the activation-induced cytidine deaminase (AID) enzyme that is essential for antibody gene diversification by V region somatic hypermutation, class-switching and gene conversion in jawed vertebrates [20]. It has been proposed that these enzymes participate in VLR gene assembly. The large numbers of donor LRR sequences and their random usage in the piece-wise assembly process contribute to an estimated potential VLR repertoire of >1014[13], which is about the size of our potential B cell repertoire [17,18].

Compartmentalized lymphocyte differentiation in jawless vertebrates

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

The two VLR loci that undergo somatic diversification are named VLRA and VLRB[18,20]. The conservation of both these genes in lamprey and hagfish suggests that they have fundamental and distinct roles in immunity. The invariant stalk regions of the VLRA and VLRB proteins share only 10–11% amino acid sequence identity, so that VLRA-specific and VLRB-specific antibodies can be used to identify the lymphocytes that bear these receptors. This type of analysis has shown that each receptor type is expressed by a discrete lymphocyte population and that the two types of lymphocytes have distinctive characteristics.

The lamprey VLRB-bearing lymphocytes resemble the B lymphocytes in jawed vertebrates. Members of the VLRB lymphocyte population can be shown to bind bacteria or foreign eukaryotic cells and to respond to these antigens by undergoing proliferation and differentiation into mature plasmacytes that secrete VLR antibodies with specificity for either protein or carbohydrate epitopes [22]. Booster immunization induces higher levels of antibody production as an indication of immunological memory. While the VLRB proteins are expressed both as cell surface receptors for antigens and as secreted antibody proteins, the VLRA proteins are expressed only in the form of cell surface receptors [23]. The VLRA-bearing lymphocytes also undergo proliferation in response to immunization, but they do not secrete their VLRA proteins after activation. Another interesting distinction between the VLRA and VLRB lymphocyte populations is the difference in their antigen receptor repertoires. Unlike VLRB lymphocytes, the VLRA lymphocytes have not been shown to bind native epitopes on the antigens to which they respond with proliferation. This is a surprising observation, as the VLRA and VLRB genes are basically similar, each is flanked by hundreds of donor LRR sequences and the latter are used randomly to generate receptor repertoires of comparable size. Both VLRA and VLRB lymphocytes undergo VLR assembly on only one allele. In addition, VLRA assembly is associated with CDA1 expression and VLRB assembly is associated with CDA2 expression, suggesting that these cytidine deaminases are involved differentially in the assembly of the two types of receptor genes. A limited analysis of the gene expression profiles of the VLRA and VLRB lymphocytes indicates that the VLRA lymphocytes express preferentially many of the genes that T lineage cells in jawed vertebrates use to begin their differentiation in the thymus and to continue their differentiation and function in peripheral lymphoid tissues. Conversely, the VLRB lymphocytes express many of the genes that are expressed typically by B cells. Given the current lack of information about the nature of the antigens recognized by VLRA lymphocytes, we stimulated lampreys with phytohaemagglutinin (PHA), a classical polyclonal mitogen that activates preferentially the T lymphocytes in jawed vertebrates. Remarkably, the lamprey VLRA lymphocytes responded preferentially to become the predominant type of lymphocytes within 1–2 weeks. Moreover, the activated VLRA lymphoblasts up-regulated their expression of the genes for the proinflammatory cytokines, macrophage migratory inhibitory factor (MIF) and IL-17. Interestingly, the IL-17 receptor (IL-17R) is expressed by the VLRB lymphocytes. Functional interactions between the two lymphocyte types are also suggested by the preferential expression of IL-8 by VLRB lymphocytes and the preferential expression of IL-8R by the VLRA lymphocytes.

Conclusion

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

This initial view of the compartmentalized differentiation of T-like and B-like lymphocytes in the lamprey provides an intriguing piece to the puzzle of how the adaptive immune system evolved. The evolution of two very different ways for generating anticipatory receptors of comparable diversity in the jawless and jawed vertebrates offers strong indirect evidence for the fitness value of adaptive immunity. The LRR-based immune system in lampreys and hagfish evolved apparently after the first round of whole genomic replication, whereas the Ig-based immune system in the jawed vertebrates derived probably from an ancestor that had undergone a second round of genomic replication [24]. The failure thus far to find VLR gene relics in jawed vertebrates also favours the idea that the two types of adaptive immunity were parallel, rather than sequential evolutionary acquisitions, around 500 million years ago.

An obvious advantage of adaptive immunity over the elaborate invertebrate strategies for innate immunity is the capacity for memory of previous encounters with infectious agents. On the other hand, the development of a randomly generated anticipatory repertoire of great diversity inevitably creates the hazard of self-reactivity and attendant autoimmunity. The orchestration of cellular and humoral immune responses by the T cells, whose TCR repertoire is shaped during development to discriminate between self and non-self antigens, provides jawed vertebrates with an important safeguard against autoimmunity. The potential for autoimmunity would, theoretically, necessitate a similar solution for the adaptive immune system in jawless vertebrates. Our findings thus suggest that dual recognition and response arms with intertwined function were fundamental to the evolution of adaptive immunity in vertebrates. Although entirely different anticipatory receptors are used by the clonally diverse lymphocytes in jawed vertebrates and jawless vertebrates [16,11], the compartmentalization of lymphocyte differentiation that is seen in both jawed and jawless vertebrates appears to be a fundamental feature of an adaptive immune system [23].

References

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions

Questions

  1. Top of page
  2. Summary
  3. Adaptive immunity in jawed vertebrates
  4. Adaptive immunity in jawless vertebrates
  5. Compartmentalized lymphocyte differentiation in jawless vertebrates
  6. Conclusion
  7. Disclosure
  8. References
  9. Questions
  • 1
    What is a satisfactory definition for adaptive versus innate immunity?
  • 2
    When did lymphocytes evolve?
  • 3
    What was the environmental pressure that led to the evolution of clonally diverse Ig- and LRR-based receptors for antigens?
  • 4
    What was the advantage of layering an adaptive immune system over an innate immune system?
  • 5
    How is autoimmunity avoided in jawless vertebrates?
  • 6
    Are histocompatibility genes/molecules used for self versus non-self discrimination in jawless vertebrates? If so, what are they?
  • 7
    Is there a thymus equivalent in jawless vertebrates? If so, where?
  • 8
    When did antigen-presenting cells and NK cells evolve during vertebrate evolution?
  • 9
    How do the innate immune components interact with the adaptive VLR system in jawless vertebrates? Once both have evolved, are they inseparable?