Biology:Adaptive immunity in jawless fish

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Jawless vertebrates, which today consist entirely of lampreys and hagfish (the Cyclostomi), have an adaptive immune system similar to that found in jawed vertebrates. The lymphocytes of the cyclostomian AIS have roles roughly equivalent to those of B-cells and T-cells, but instead of variable immunoglobulins and T-cell receptors they use variable lymphocyte receptors to generate the diversity required for an adaptive immune system.[1]

Two lymphocyte lineages were identified in 2009, expressing two different kinds of VLR, VLRA and VLRB. They resembled α/β T and B cells respectively,[1] in function and pathway of differentiation. This suggests that although the two branches of extant vertebrates had adopted different antigen-recognition receptors, the division of labor between T-like and B-like lymphocytes was already present in their common ancestor.[2] Discovery of VLRC+ cells in 2013, which resembled γ/δ T cells, further suggested that a tripartite division of labor had been present.[3] As of 2026, six VLR classes have been discovered in lampreys (VLRA through VLRF) and three have been discovered in hagfishes (VLRA through VKRC).[4] The identically-named classes correspond to each other, suggesting the ancestral cyclostomian did have three classes.[5]

Antigen receptors

Jawless vertebrates do not have immunoglobulins (Igs), the key proteins to B-cells and T-cells. However, they do possess a system of leucine-rich repeat (LRR) proteins that make up variable lymphocyte receptors (VLRs). This system can produce roughly the same number of potential receptors that the Ig-based system found in jawed vertebrates can.[6] Instead of using recombination-activating genes (RAGs) to randomly incorporate segments like bony fish Igs, genes coding for VLRs are assembled randomly via a process resembling gene conversion, mediated by a family of cytidine deaminases known as APOBEC.[7][8][lower-alpha 1] Cytidine deaminase 1 (CDA1) is associated with the assembly of VLRA and VLRC and cytidine deaminase 2 (CDA2) appears to assemble VLRB.[1][3]

The product of VLR gene conversion is a functional gene expressing a VLR protein. The VLR typically consists of a signal peptide (SP), an N-terminal capping domain (LRRNT), a largely invariant 24-residue first LRR segment (LRR1), up to 9 24-residue variable LRRs (LRRV), a final truncated LRR called the connecting peptide (CP), a C-terminal capping domain including a stalk (LRRCT).[10] This gene is assembled starting from a "skeleton" gene in the germline genome, which contains the promoters, the SP+LRRNT, a large gap, followed by LRRCT. Each VLR type uses its own skeleton gene. (The skeletons vary in their domain composition: VLRB and VLRD skeletons only have part of LRRNT; VLRE skeleton includes part of LRR1; VLRB skeleton has a split LRRCT; VLRF only has the C-terminal part of LRRCT.) Serial gene conversion replaces the gap with LRR1/LRRV/CP segments from donor cassettes located elsewhere in the genome. Some cassettes are shared among multiple VLR types, others are specific for one type only.[11][4]

It is unclear whether there is a system in place to weed out lymphocytes expressing self-reactive VLRs in the cyclostomian AIS. Selection for length (number of LRRVs) and diversity of the N-terminal domain has been identified, however.[12]

Lymphocytes

The gene expression profiles of lymphocytes (also "lymphocyte-like cells", LLCs) in jawless vertebrates indicate that VLRB+ LLCs and B cells, VLRA+ LLCs and α/β T cells, and VLRC+ LLCs and γ/δ T cells each share a common ancestor.[2] Like B cells and T cells, the development of VLRB+ LLCs is spatially separated from the development of VLRA+ and VLRC+ LLCs. VLRB+ LLCs and B cells develop in hematopoietic tissues: VLRB+ LLCs develop in the typhlosole and kidneys and B cells develop in bone marrow. VLRA+ and VLRC+ LLCs develop in a thymus-like organ called the thymoid, similar to T cells developing in the thymus.[13] The expression of VLRA and VLRC are mutually exclusive, much like the α/β and γ/δ TCRs.[14]

There is also a population of triple-negative (VLR{A,B,C}-) lymphocytes that express none of these types. The additional lymprey types (VLRD/E/F) show the highest expression in these cells, but VLRD/E/F also show a little bit of expression in VLRA+ and VLRC+ cells. These additional types are therefore also considered "T-like".[11][4]

Functional characterization

VLRB molecules and LLBs can directly bind to antigens and VLRB-transfected cells secrete VLRB protein products, similar to B cells in jawed vertebrates. VLRA+ LLCs were unable to bind Bacillus anthracis, Escherichia coli, Salmonella typhimurium, or Streptococcus pneumoniae before or after immunization, suggesting that VLRAs require antigen processing like TCRs.[1] However, MHCs or MHC-like molecules that could present processed antigens have not been found in lampreys,[15] and some VLRAs expressed in yeast were able to directly bind to antigens.[16] The antigen binding of VLRCs has not been studied.[17] However, the VLRC gene is close in proximity and sequence to the VLRA gene and the two are often co-expressed in LLCs, suggesting that both are TCR-like receptors.[3]

Similar systems in invertebrates

VLR-like proteins have been identified in the amphixous Branchiostoma floridae. One identified protein specifically recognizes Gram-positive bacteria and is likely highly expressed in the gill, a potential immune organ. There is no evidence of it being somatically variable.[18]

A VLR-like gene in the Chinese mitten crab Eriocheir sinensis has ten different isoforms from alternative splicing, with different antigen specificities. This offers a limited degree of antigen receptor diversity. Many organisms without an adaptive immune system have expansions in their pattern recognition receptors to provide diversity and this is one example.[19]

References

  1. ↑ The B cells of jawed vertebrates use an APOBEC called AID to perform somatic hypermutation, which involves randomly changing bases through error-prone DNA repair. In many of them, the process also leads to somatic gene conversion.[9]
  1. ↑ 1.0 1.1 1.2 1.3 Guo, Peng; Hirano, Masayuki; Herrin, Brantley R.; Li, Jianxu; Yu, Cuiling; Sadlonova, Andrea; Cooper, Max D. (2009-05-27). "Dual nature of the adaptive immune system in lampreys". Nature 459 (7248): 796–801. doi:10.1038/nature08068. ISSN 0028-0836. PMID 19474790. Bibcode: 2009Natur.459..796G. 
  2. ↑ 2.0 2.1 Kasamatsu, Jun (January 2013). "Evolution of innate and adaptive immune systems in jawless vertebrates" (in en). Microbiology and Immunology 57 (1): 1–12. doi:10.1111/j.1348-0421.2012.00500.x. ISSN 0385-5600. PMID 22924515. 
  3. ↑ 3.0 3.1 3.2 Hirano, Masayuki; Guo, Peng; McCurley, Nathanael; Schorpp, Michael; Das, Sabyasachi; Boehm, Thomas; Cooper, Max D. (2013-08-11). "Evolutionary implications of a third lymphocyte lineage in lampreys". Nature 501 (7467): 435–438. doi:10.1038/nature12467. ISSN 0028-0836. PMID 23934109. Bibcode: 2013Natur.501..435H. 
  4. ↑ 4.0 4.1 4.2 Das, Sabyasachi; Fontenla-Iglesias, Francisco; Hirano, Masayuki; Morimoto, Ryo; Au-Yeung, Byron B.; Wang, Yashuo; Li, Weiming; Boehm, Thomas et al. (15 July 2025). "Variable lymphocyte receptor F is generated via somatic diversification and expressed by lamprey T-like cells". Nature Communications 16 (1). doi:10.1038/s41467-025-61187-1. PMID 40664669. Bibcode: 2025NatCo..16.6503D. 
  5. ↑ Li, J; Das, S; Herrin, BR; Hirano, M; Cooper, MD (10 September 2013). "Definition of a third VLR gene in hagfish.". Proceedings of the National Academy of Sciences of the United States of America 110 (37): 15013–8. doi:10.1073/pnas.1314540110. PMID 23980174. Bibcode: 2013PNAS..11015013L. 
  6. ↑ Cooper, Max D.; Alder, Matthew N. (2006-02-24). "The evolution of adaptive immune systems". Cell 124 (4): 815–822. doi:10.1016/j.cell.2006.02.001. ISSN 0092-8674. PMID 16497590. Bibcode: 2006Cell..124..815C. 
  7. ↑ Hirano, Masayuki (August 2015). "Evolution of vertebrate adaptive immunity: immune cells and tissues, and AID/APOBEC cytidine deaminases". BioEssays 37 (8): 877–887. doi:10.1002/bies.201400178. ISSN 1521-1878. PMID 26212221. 
  8. ↑ Boehm, T; McCurley, N; Sutoh, Y; Schorpp, M; Kasahara, M; Cooper, MD (2012). "VLR-based adaptive immunity.". Annual Review of Immunology 30: 203–20. doi:10.1146/annurev-immunol-020711-075038. PMID 22224775. 
  9. ↑ Mallaby, Jessica; Mwangi, William; Ng, Joseph; Stewart, Alexander; Dorey-Robinson, Daniel; Kipling, David; Hershberg, Uri; Fraternali, Franca et al. (1 January 2023). "Diversification of immunoglobulin genes by gene conversion in the domestic chicken ( Gallus gallus domesticus)". Discovery Immunology 2 (1). doi:10.1093/discim/kyad002. PMID 38567069. 
  10. ↑ Velikovsky, CA; Deng, L; Tasumi, S; Iyer, LM; Kerzic, MC; Aravind, L; Pancer, Z; Mariuzza, RA (July 2009). "Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen.". Nature Structural & Molecular Biology 16 (7): 725–30. doi:10.1038/nsmb.1619. PMID 19543291. 
  11. ↑ 11.0 11.1 Das, S; Boehm, T; Holland, SJ; Rast, JP; Fontenla-Iglesias, F; Morimoto, R; Valadez, JG; Heimroth, RD et al. (29 August 2023). "Evolution of two distinct variable lymphocyte receptors in lampreys: VLRD and VLRE.". Cell Reports 42 (8). doi:10.1016/j.celrep.2023.112933. PMID 37542721. 
  12. ↑ Holland, SJ; Gao, M; Hirano, M; Iyer, LM; Luo, M; Schorpp, M; Cooper, MD; Aravind, L et al. (14 October 2014). "Selection of the lamprey VLRC antigen receptor repertoire.". Proceedings of the National Academy of Sciences of the United States of America 111 (41): 14834–9. doi:10.1073/pnas.1415655111. PMID 25228760. Bibcode: 2014PNAS..11114834H. 
  13. ↑ Bajoghli, Baubak; Guo, Peng; Aghaallaei, Narges; Hirano, Masayuki; Strohmeier, Christine; McCurley, Nathanael; Bockman, Dale E.; Schorpp, Michael et al. (2011-02-03). "A thymus candidate in lampreys" (in En). Nature 470 (7332): 90–94. doi:10.1038/nature09655. ISSN 0028-0836. PMID 21293377. Bibcode: 2011Natur.470...90B. 
  14. ↑ Kishishita, Natsuko; Nagawa, Fumikiyo (March 2014). "Evolution of adaptive immunity: implications of a third lymphocyte lineage in lampreys". BioEssays 36 (3): 244–250. doi:10.1002/bies.201300145. ISSN 1521-1878. PMID 24853392. 
  15. ↑ Mayer, Werner E.; Uinuk-ool, Tatiana; Tichy, Herbert; Gartland, Lanier A.; Klein, Jan; Cooper, Max D. (2002-10-29). "Isolation and characterization of lymphocyte-like cells from a lamprey" (in en). Proceedings of the National Academy of Sciences 99 (22): 14350–14355. doi:10.1073/pnas.212527499. ISSN 0027-8424. PMID 12388781. Bibcode: 2002PNAS...9914350M. 
  16. ↑ Deng, Lu; Velikovsky, C. Alejandro; Xu, Gang; Iyer, Lakshminarayan M.; Tasumi, Satoshi; Kerzic, Melissa C.; Flajnik, Martin F.; Aravind, L. et al. (2010-07-27). "A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey" (in en). Proceedings of the National Academy of Sciences 107 (30): 13408–13413. doi:10.1073/pnas.1005475107. ISSN 0027-8424. PMID 20616002. Bibcode: 2010PNAS..10713408D. 
  17. ↑ Boehm, Thomas; Hirano, Masayuki; Holland, Stephen J.; Das, Sabyasachi; Schorpp, Michael; Cooper, Max D. (2018-04-26). "Evolution of Alternative Adaptive Immune Systems in Vertebrates" (in en). Annual Review of Immunology 36 (1): 19–42. doi:10.1146/annurev-immunol-042617-053028. ISSN 0732-0582. PMID 29144837. 
  18. ↑ Cao, DD; Liao, X; Cheng, W; Jiang, YL; Wang, WJ; Li, Q; Chen, JY; Chen, Y et al. (29 January 2016). "Structure of a variable lymphocyte receptor-like protein from the amphioxus Branchiostoma floridae.". Scientific Reports 6. doi:10.1038/srep19951. PMID 26821753. Bibcode: 2016NatSR...619951C. 
  19. ↑ Xu, Y; Yang, Y; Zheng, J; Cui, Z (2022). "Alternative splicing derived invertebrate variable lymphocyte receptor displays diversity and specificity in immune system of crab Eriocheir sinensis.". Frontiers in Immunology 13. doi:10.3389/fimmu.2022.1105318. PMID 36999166. 

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