Major histocompatibility complex (MHC) and T cell receptors

Jennifer Nyland, PhDOffice: Bldg#1, Room B10

Phone: 733-1586Email: jnyland@uscmed.sc.edu

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

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

Structure of MHC class I

• Two polypeptide chains– Long α chain and

short β

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

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

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

Structure of MHC class II

• Two polypeptide chains– α and β– approx equal length

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

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)

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

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

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

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

T cell receptor (TCR)

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

Structure of the TCR (αβ)

• Heterodimer– α and β chains– approx equal length

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

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

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

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

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

The “immunological synapse”

• Specificity for Ag is solely in TCR

• Accessory molecules are invariant

• Cytokines change expression levels

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

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