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Class Ib Proteins: similar structures with diverse functions

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Have a binding cleft in a1 and a2 domains. Some highly polygenic. Usually limited polymorphism ... Associates with b2m and transferrin receptor ... – PowerPoint PPT presentation

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Title: Class Ib Proteins: similar structures with diverse functions


1
Class Ib Proteins similar structures with
diverse functions Russell Salter February 14,
2007
2
  • Class Ib proteins
  • Share structural homology with class Ia
  • Some can bind b2m
  • Have a binding cleft in a1 and a2 domains
  • Some highly polygenic
  • Usually limited polymorphism

3
HLA-Hfe
  • Associates with b2m and transferrin receptor
  • Mutation in gene affecting protein folding
    interferes with iron uptake by cell in hereditary
    hemochromatosis
  • Iron binding site is in the groove

4
MIC-A, MIC-B, ULBP (human) RAE-1 (mouse)
  • Do not associate with b2m or peptides
  • Upregulated in response to cellular stress,
    heat shock, HCMV infection, transformation
  • Promoter similar to hsp70
  • Over 50 alleles, some associated with autoimmune
    disease
  • Expressed on gut epithelium, some tumors
  • Ligand for NKG2D

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6
HLA-G
  • Found on placental trophoblast cells, few other
    normal tissues
  • Protects fetus from maternal immune responses?
    Found in decreased amounts on trophoblasts from
    spontaneous abortions relative to normal fetus
  • Expressed on many tumors-protects against NK
    lysis

7
HLA-G
  • Interacts with ILT2, ILT4, 2DL4 on NK cells,
    monocytes, dendritic cells, some T and B cells
  • Associates with HCMV protein US3 which retains
    HLA-G in ER

8
CTB Cytotrophoblast
Chorion CTB-fetal Decidual cells-maternal
Hunt, J. Imm. Rev 2006
9
Alternative splicing generates HLA-G variants
Hunt, J. Imm. Rev 2006
10
Hunt, J. Imm. Rev 2006
11
Hunt, J. Imm. Rev 2006
12
HLA-E (human) Qa-1(mouse)
  • Binds b2m and is retained in the ER initially
  • Expressed on cell surface only after binding
    peptides derived from signal sequences of class I
    MHC-HLA-A,B,C, G
  • HCMV UL40 upregulates HLA-E expression

13
HLA-E (human) Qa-1(mouse) continued
  • Interacts with CD94/NKG2A or CD94/NKG2B on NK
    cells, turning off lytic function
  • In addition, HLA-E can bind peptides from some
    intracellular pathogens and present to CD8 T
    cells

14
TCR recognition of HLA-E is not unusual
structurally
HLA-E ssUL40 from CMV
HLA-B8LC30 peptide
Hoare et al Nat Immunol. 7256, March 2006
15
H-2M3 (mouse only)
  • Binds 7-8 aa peptides with N-formyl methionine
    at N-terminus (and b2m)
  • Intracellular presence of peptides from bacteria
    or mitochondria induces transport of H-2M3 to PM
  • CD8 T cells recognize bacterial peptides with
    H-2M3
  • T cell responses show rapid kinetics in primary
    responses, but have weak memory characteristics

16
Diverse peptide ligand structures bind class Ia
and class Ib proteins
17
CD1 family
  • Human CD1a, b, c, d, e Mouse CD1d1, d2
  • Expressed on dendritic cells, limited other
    tissues
  • Bind b2m and non-peptide antigen in binding cleft

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Comparison of different MHC molecules
21
Structures of CD1 binding lipids
22
Binding cleft structures
23
Ttunnel
24
Glycolipid-binding cleft interactions of CD1
proteins
25
Tissue Antigens 60337-353, 2002
26
Alternative pathway for CD1e and CD1d
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28
Saposins transfer lipids into CD1 molecules
29
Dendritic cell expression of CD1 proteins
30
CD1 group I responses
31
CD1 group 2 responses
32
a-galactosylceramide induced immune responses
33
CD1d mediated anti-tumor immunity
34
CD1d mediated prevention of diabetes in NOD mouse
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