major histocompatability complex (mhc) and t cell receptors
TRANSCRIPT
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Major histocompatibility complex (MHC) and T cell receptors
Jennifer Nyland, PhDOffice: Bldg#1, Room B10
Phone: 733-1586Email: [email protected]
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Teaching objectives
• To give an overview of role of MHC in immune response
• To describe structure & function of MHC• To describe structure & function of TCR• To discuss the genetic basis for generation of
diversity in TCR• To describe the nature of immunological synapse
and requirements for T cell activation
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Role of MHC in immune response
• TCR recognizes Ag presented in MHC– Context is important– Binding of Ag peptides in non-covalent
• Two types of MHC (class I and class II) are recognized by different subsets of T cells– CTL recognizes Ag peptide in MHC class I– T-helper recognizes Ag peptide in MHC class II
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Structure of MHC class I
• Two polypeptide chains– Long α chain and
short β
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Structure of MHC class I
• Four regions– Cytoplasmic contains sites
for phosphorylation and binding to cytoskeleton
– Transmembrane contains hydrophobic AAs
– Highly conserved α3 domain binds CD8
– Highly polymorphic peptide binding region formed by α1 and α2
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Structure of MHC class I Ag-binding groove
• Groove composed of – α helix on 2 opposite
walls– Eight β sheets as floor
• Residues lining floor are most polymorphic
• Groove binds peptides 8-10 AA long
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Structure of MHC class I Ag-binding groove
• Specific amino acids on peptide are required for “anchor site” in the groove– Many peptides can bind– Interactions at N and C-terminus are critical and
“lock” peptide in grove– Center of peptide bulges out for presentation– Consideration in vaccine development
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Structure of MHC class II
• Two polypeptide chains– α and β– approx equal length
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Structure of MHC class II
• Four regions– Cytoplasmic contains sites
for phosphorylation and binding to cytoskeleton
– Transmembrane contains hydrophobic AAs
– Highly conserved α2 and β2 domains binds CD4
– Highly polymorphic peptide binding region formed by α1 and β1
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Structure of MHC class II Ag-binding groove
• Groove composed of – α helix on 2 opposite
walls– Eight β sheets as floor– Both α1 and β1 make up
groove• Residues lining floor are
most polymorphic• Groove binds peptides
13-25 AA long (some outside groove)
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Important aspects of MHC
• Individuals have a limited number of MHC alleles for each class
• High polymorphism in MHC for a species• Alleles for MHC genes are co-dominant– Each MHC gene product is expressed on surface of
individual cell
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Important aspects of MHC
• Each MHC has ONE peptide binding site– But each MHC can bind many different peptides– Only one at a time– Peptide binding is “degenerate”
• MHC polymorphism is determined in germline– NO recombination mechanisms for creating
diversity in MHC• Peptide must bind with individual’s MHC to
induce immune response
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Important aspects of MHC• How do peptides
get into MHC groove?– Class I: peptides
in cytosol associate with MHC
– Class II: peptides from within vesicles associate with MHC
golgi
ERClass I
Cytoplasmic peptide
Class II
Ii chain
Peptide in vesicleDisplaces Ii chain
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Important aspects of MHC
• MHC molecules are membrane-bound– Recognition by Ts requires cell-cell contact
• Mature Ts must have TCR that recognizes particular MHC
• Cytokines (especially IFN-γ) increase expression of MHC
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T cell receptor (TCR)
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Role of TCR in immune response
• Surface molecule on Ts• Recognize Ag presented in MHC context• Similar to Immunoglobulin• Two types of TCR– α β: predominant in lymphoid tissues– γ δ: enriched at mucosal surfaces
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Structure of the TCR (αβ)
• Heterodimer– α and β chains– approx equal length
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Structure of the TCR (αβ)
• Regions– Short cytoplasmic tail-
cannot transduce activation signal
– Transmembrane with hydrophobic AAs
– Both α and β have a variable (V) and constant (C) region
– V region is hypervariable, determines Ag specificity
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Important aspects of TCR
• Each T cell has TCR of only ONE specificity– Allelic exclusion
• αβ TCR recognizes Ag only in the context of cell-cell interaction and in correct MHC context
• γδ TCR recognizes Ag in MHC-independent manner– Response to certain viral and bacterial Ag
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Genetic basis for receptor generation• Accomplished by recombination of V, D and J
gene segments– TCR β chain genes have V, D, and J– TCR α chain genes have V and J
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TCR and CD3 complex
• TCR is closely associated with CD3 complex– Group of 5 proteins– Commonly called
“invariant” chains of TCR• Role of CD3 complex– CD3 necessary for cell
surface expression of TCR
– transduces signal after Ag interaction with TCR
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The “immunological synapse”
• TCR-MHC interaction is not strong
• Accessory molecules stabilize interaction– CD4/MHC class II or
CD8/MHC class I– CD2/LFA-3– LFA-1/ICAM-1
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The “immunological synapse”
• Specificity for Ag is solely in TCR
• Accessory molecules are invariant
• Cytokines change expression levels
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The “immunological synapse”
• Co-stimulation is also necessary for activation of T cells– CD28/CD80 or CD86
• CTLA-4 on T cells can also ligate CD80/CD86– Inhibitory signal– downregulation
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Key steps in T cell activation
• APC must process and present peptides to Ts• Ts must receive co-stimulatory signal• Accessory adhesion molecules stabilize
binding of TCR and MHC• Signal from cell surface is transmitted to
nucleus• Cytokines produced help drive cell
proliferation