The role of the T cell specific adapter protein (TSAd) in T cell activation and autoimmunity

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The role of the T cell specific adapter protein
(TSAd) in T cell activation and autoimmunity

• Stine Granum
• NSI annual meeting
• 26. November 2003

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TSAd is encoded by the SH2D2A gene
SH2
SH2-ligands
50 kDa
SH3 ligands
The SH2D2A gene is located close to the CD1
region on chromosome 1q21.
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TSAd is expressed in activated T cells
Sundvold et al 2000
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The SH2D2A promoter contains a polymorphic GA
repeat
Short alleles has been found to be increased in
frequency among muliple sclerosis (MS) patients.
Dai et al 2001
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The SH2D2A genotype influences level of TSAd
expression
Western blot
Dai et al 2001
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Lck is the first (?) kinase to be activated
when TCR is triggered
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Intracellular signaling events triggered by TCR
Ca2
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TSAd inhibits hyperactive Lck Y505F expressed in
Jurkat T cells
Lck Y505F TSAd
Lck Y505F
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TSAd may interact with Lck on several different
positions
Lck
TSAd
Granum Sundvold-Gjerstad, manuscript
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(No Transcript)
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The Y8910F mutant shows normal LAT and Y319 Zap70
phosphorylation
TSAd
TSAd del exon 7
TSAd Y(7-10)F
TSAd Y(8910)F
Granum Sundvold-Gjerstad, manuscript
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TSAd-KO mice have enlarged spleens and increased
numbers of activated T cells
TSAd -/-
Events
? Susceptible to lupus-like autoimmune disease ?
Defective T cell death in vivo
Drappa et al, JEM 2003
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Conclusion

• Polymorphism influencing TSAd expression level is
  associated to MS
• TSAd inhibits the hyperactive LckY505F.
• The Y8910F mutant shows normal Y319 Zap70 and
  LAT phosphorylation, indicating that one or
  several of the three C-terminal tyrosines in TSAd
  is important for the inhibitory effect of TSAd on
  Lck activity
• TSAd-KO mice display spontaneously systemic
  lupus-like (SLE) autoimmune disease.

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Contributors to this project

• MS genetics
• Hanne F. Harbo
• Ke-Zheng Dai
• Anne Spurkland
• Elisabeth G. Celius
• Bodvar Vandvik
• Frode Vartdal
• Nordic study group on MS genetics

• T cell activation
• Vibeke Sundvold
• Stine Granum
• Lise Berven
• Knut Martin Torgersen
• Tor Lea
• Anne Spurkland
• Tomas Mustelin