Major histocompatibility complex MHC and T cell receptors

Major histocompatibility complex (MHC) and T cell receptors Jennifer Nyland, Ph. D Office: Bldg#1, Room B 10 Phone: 733 -1586 Email: 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 α 3 domain binds CD 8 – Highly polymorphic peptide binding region formed by α 1 and α 2

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 α 2 and β 2 domains binds CD 4 – Highly polymorphic peptide binding region formed by α 1 and β 1

Structure of MHC class II Ag-binding groove • Groove composed of – α helix on 2 opposite walls – Eight β sheets as floor – Both α 1 and β 1 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? e d i t ep ic p Cy golgi asm l p to Class I – Class I: peptides in cytosol associate with MHC Peptide in vesicle– Class II: peptides Displaces Ii chain from within vesicles associate with MHC Ii chain Class II ER

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 tailcannot 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 CD 3 complex • TCR is closely associated with CD 3 complex – Group of 5 proteins – Commonly called “invariant” chains of TCR • Role of CD 3 complex – CD 3 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 – CD 4/MHC class II or CD 8/MHC class I – CD 2/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 – CD 28/CD 80 or CD 86 • CTLA-4 on T cells can also ligate CD 80/CD 86 – 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