Class Ib Proteins: similar structures with diverse functions

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Class Ib Proteins similar structures with
diverse functions Russell Salter February 20,
2008
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• 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

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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

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MIC-A, MIC-B, ULBP (human) RAET-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
• Ligands for NKG2D

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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

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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

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CTB Cytotrophoblast
Chorion CTB-fetal Decidual cells-maternal
Hunt, J. Imm. Rev 2006
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Alternative splicing generates HLA-G variants
Hunt, J. Imm. Rev 2006
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Hunt, J. Imm. Rev 2006
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Hunt, J. Imm. Rev 2006
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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

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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

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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
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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

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Diverse peptide ligand structures bind class Ia
and class Ib proteins
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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
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Structures of CD1 binding lipids
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Binding cleft structures
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Ttunnel
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Glycolipid-binding cleft interactions of CD1
proteins
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Tissue Antigens 60337-353, 2002
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Alternative pathway for CD1e and CD1d
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Saposins transfer lipids into CD1 molecules
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Dendritic cell expression of CD1 proteins
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CD1 group I responses
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CD1 group 2 responses
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a-galactosylceramide induced immune responses
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CD1d mediated anti-tumor immunity
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CD1d mediated prevention of diabetes in NOD mouse