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Transcript
The evolution of the adaptive immune system Lucas Kemper 17.01.2011 Introduction Lamprey Shark big bang theory Jawless vertebrate conventional adaptive immunity Jawed vertebrate 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) invertebrates jawless vertebrates Introduction jawed vertebrates Conventional adaptive immunity RAG mediated rearranging of antigen receptors further mechanisms for receptor diversification MHC molecules 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 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 RAG mediated rearranging of antigen receptors V(D)J recombination – the origin of this mechanism RAG-like transposon first mechanism leading to variable immune receptors 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 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 Integration in ancestral immunoglobulin gene locus* Gene segments in Ig and TCR loci differentiation Recombination and gene duplication RAG location outside of Ig and TCR loci locus duplication tandem duplication RSS elements remained in Ig and TCR loci Further mechanisms for receptor diversification jawed vertebrates have many Lamprey Shark novel mechanisms and molecules that are involved in adaptive immunity compared with jawless fish Jawless vertebrate Jawed vertebrate Expansion of the potential of V D J recombination 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 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 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 Igs and BCR arose before TCR and MHC or antigen processing and explenatation for the development presentation by MHC of an TCR-MHC system maybe derived from phagocytosis and lysosomal processing using VDJ recombination to recognize intracellular antigens End of the story? Lamprey But I am not helpless! I can also mount an adaptive immune response in the absence of BCR, TCR and MHC Shark Ha, I am so cool! A convergent adaptive IS of jawless vertebrates Jawless vertebrates Lamprey Jawed Sharkvertebrates A convergent adaptive IS of jawless vertebrates Jawless vertebrates main features of the convergent adaptive immune system 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 Conclusions 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” invertebrates jawless vertebrates BCR–TCR–MHC-based system is more complex jawed vertebrates Conclusions 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? invertebrates jawless vertebrates BCR–TCR–MHC-based system is more complex jawed vertebrates Thank you