Lucas Kemper

17.01.2011

The evolution of theadaptive immune system

Introduction

Lamprey Shark

Jawless vertebrate Jawed vertebrate

big bang

theory

conventionaladaptiveimmunity

Introduction

Lamprey Shark

What does he hasthat I don’t have?

I have:

RAG mediated rearrangingof antigen receptors

(for my B and T cells)

further mechanisms for receptor diversification

MHC molecules

(and much more)

Introduction

jawed vertebratesjaw

less

vert

ebra

tes

invertebrates

RAG mediated rearrangingof antigen receptors

further mechanisms for receptor diversification

MHC molecules

Conventional adaptiveimmunity

RAG mediated rearranging of antigen receptorsV(D)J recombination – state of the art

locus of TCR α-chain

in germline-DNA

locus ofTCR β-chain

in germline-DNA

randomly recombined DNA

randomly recombined DNA

αβ T cell receptor

RAG mediated rearranging of antigen receptorsV(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

RAG mediated rearranging of antigen receptorsV(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 mechanismleading to variable immune receptors

excision of transposon

imprecise sealing of the gap

clonaly diverse specifities

RAG mediated rearranging of antigen receptorsV(D)J recombination – the origin of this mechanism

RAG-like transposon

Common ancestor of all jawed vertebrates

Integration in ancestral immunoglobulin gene locus*

first mechanismleading to variable immune receptors

Recombination andgene duplication

RAG location outsideof Ig and TCR loci

RSS elementsremained in

Ig and TCR locilocus duplicationtandem duplication

differentiation

Gene segments inIg and TCR loci

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

Lamprey Shark

Jawless vertebrate Jawed vertebrate

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

MHC molecules

What was first?

hen or egg

rearranging αβTCR or antigen processing andpresentation by MHC

MHC molecules present antigen to αβTCR on T cells

MHC molecules

What was first?

MHC molecules present antigen to αβTCR on T cells

rearranging αβTCR or antigen processing andpresentation 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 arosebefore TCR and MHC

explenatation for the developmentof an TCR-MHC system

maybe derived from phagocytosis and lysosomal processing

using VDJ recombination to recognize intracellular antigens

End of the story?

Lamprey Shark

Ha, I am so cool!But I am not helpless!

Lamprey

I can also mount anadaptive immune response

in the absence ofBCR, TCR and MHC

SharkLamprey

A convergent adaptive IS of jawless vertebratesJawless vertebrates Jawed vertebrates

A convergent adaptive IS of jawless vertebratesJawless vertebrates main features of the convergent

adaptive immune system

variable lymphocyte receptor = VLR

leucin rich repeats = LRR

generation of diversity by rearrangingLRR 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 befunctionally similar to the T and B cells

jawed vertebratesjaw

les

sv

ert

eb

rate

s

invertebrates

Conclusions

BCR–TCR–MHC‑based systemis 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”

jawed vertebratesjaw

les

sv

ert

eb

rate

s

invertebrates

Conclusions

BCR–TCR–MHC‑based systemis 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 evolutionarypressures for adaptive immunity?

large predatory jawed vertebrateshave usualy few offsprings

adaptive immune system forhigher surival rate of offsprings?

Thank you