1. Lucas Kemper 17.01.2011 The evolution of the adaptive immune system

2. Introduction LampreyShark Jawless vertebrateJawed vertebrate big bang theory conventional adaptive immunity

3. Introduction LampreyShark What does he has that I don’t have? I have: RAG mediated rearranging of antigen receptors (for my B and T cells) further mechanisms for receptor diversification MHC molecules (and much more)

4. Introduction jawed vertebrates jawless vertebrates invertebrates RAG mediated rearranging of antigen receptors further mechanisms for receptor diversification MHC molecules Conventional adaptive immunity

5. RAG mediated rearranging of antigen receptors V(D)J recombination – state of the art locus of TCR α-chain in germline-DNA locus of TCR β-chain in germline-DNA randomly recombined DNA αβ T cell receptor

6. RAG mediated rearranging of antigen receptors V(D)J recombination – state of the art RAG complex binds recombination signal sequence RAG complexes arrange next to each other RAG complex cleaves DNA and hairpins are formed Endonucleases open the hairpin randomly Random nucleotides are added by TdT and/or deleted by endonucleases Ligation of DNA terminal deoxynucleotidyl transferase (TdT) germline configuration

7. RAG mediated rearranging of antigen receptors V(D)J recombination – the origin of this mechanism RAG-like transposon Common ancestor of all jawed vertebrates Integration in ancestral immunoglobulin gene locus* *nature unclear *maybe innate immune receptor first mechanism leading to variable immune receptors  excision of transposon  imprecise sealing of the gap  clonaly diverse specifities

8. RAG mediated rearranging of antigen receptors V(D)J recombination – the origin of this mechanism RAG-like transposon Common ancestor of all jawed vertebrates Integration in ancestral immunoglobulin gene locus* first mechanism leading to variable immune receptors Recombination and gene duplication RAG location outside of Ig and TCR loci RSS elements remained in Ig and TCR loci locus duplication tandem duplication differentiation Gene segments in Ig and TCR loci

9. Further mechanisms for receptor diversification Expansion of the potential of V D J recombination jawed vertebrates have many novel mechanisms and molecules that are involved in adaptive immunity compared with jawless fish LampreyShark Jawless vertebrateJawed vertebrate

10. Further mechanisms for receptor diversification terminal deoxynucleotidyl transferase (TdT) germline configuration terminal deoxynucleotidyl transferase (TdT) lymphocyte-specific template-independent DNA polymerase introduces untemplated nucleotides at the junctions of V, D and J segments not found in jaweless vertebrates or below thereby TdT increases diversity

11. MHC molecules What was first? henoregg rearranging αβTCRorantigen processing and presentation by MHC MHC molecules present antigen to αβTCR on T cells

12. MHC molecules What was first? MHC molecules present antigen to αβTCR on T cells rearranging αβTCRorantigen processing and presentation by MHC αβTCR and MHC appeared at the same time in evolution no αβTCR and MHC outside of jawed vertebrates therefore it is difficult to answer what was first Igs and BCR arose before TCR and MHC explenatation for the development of an TCR-MHC system  maybe derived from phagocytosis and lysosomal processing  using VDJ recombination to recognize intracellular antigens

13. End of the story? LampreyShark Ha, I am so cool! But I am not helpless! Lamprey I can also mount an adaptive immune response in the absence of BCR, TCR and MHC

14. Shark Lamprey A convergent adaptive IS of jawless vertebrates Jawless vertebratesJawed vertebrates

15. A convergent adaptive IS of jawless vertebrates Jawless vertebrates main features of the convergent adaptive immune system variable lymphocyte receptor = VLR leucin rich repeats = LRR generation of diversity by rearranging LRR modules into the VLR gene RAG-independent process germline VLR lacks LRR modules a single VLR gene can have combinatorial diversity comparable to that of Igs Two VLR genes known (membrane-bound and secreted) two populations of lymphoid cells that seem to be functionally similar to the T and B cells

16. jawed vertebrates jawless vertebrates invertebrates Conclusions BCR–TCR–MHC ‑ based system is more complex jawless and jawed fish both have an AIS based on different gene families RAG transposon had major role in the emergence of the jawed vertebrate AIS What about the big bang theory? Still holds true for conventional adaptive immunity (BCR, TCR, MHC) but “could be more a set of observations made from a limited phylogenetic sampling and mechanistic focus than a true representation of rapid evolution”

17. jawed vertebrates jawless vertebrates invertebrates Conclusions BCR–TCR–MHC ‑ based system is more complex jawless and jawed fish both have an AIS based on different gene families RAG transposon had major role in the emergence of the jawed vertebrate AIS What about the evolutionary pressures for adaptive immunity? large predatory jawed vertebrates have usualy few offsprings adaptive immune system for higher surival rate of offsprings?

18. Thank you