Lucas Kemper 17.01.2011

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

2. Introduction Lamprey Shark big bang theory conventional adaptive immunity Jawless vertebrate Jawed vertebrate

3. Introduction Lamprey Shark I have: What does he has that I don’t 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 jawless vertebrates Conventional adaptive immunity jawed vertebrates invertebrates RAG mediated rearranging of antigen receptors further mechanisms for receptor diversification MHC molecules

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

6. RAG mediated rearranging of antigen receptors V(D)J recombination – state of the art germline configuration terminal deoxynucleotidyl transferase (TdT) 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

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

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

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

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

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

12. MHC molecules MHC molecules present antigen to αβTCR on T cells What was first? 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 rearranging αβTCR or antigen processing and presentation by MHC 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? Lamprey Shark Lamprey But I am not helpless! Ha, I am so cool! I can also mount an adaptive immune response in the absence of BCR, TCR and MHC

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

15. A convergent adaptive IS of jawless vertebrates main features of the convergent adaptive immune system Jawless vertebrates germline VLR lacks LRR modules generation of diversity by rearranging LRR modules into the VLR gene RAG-independent process 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 variable lymphocyte receptor = VLR leucin rich repeats = LRR

16. Conclusions jawless and jawed fish both have an AIS based on different gene families BCR–TCR–MHC‑based system is more complex RAG transposon had major role in the emergence of the jawed vertebrate AIS jawless vertebrates invertebrates jawed vertebrates 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. Conclusions jawless and jawed fish both have an AIS based on different gene families BCR–TCR–MHC‑based system is more complex RAG transposon had major role in the emergence of the jawed vertebrate AIS jawless vertebrates invertebrates jawed vertebrates 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