Major Histocompatibility Complex (MHC) and T Cell Receptors

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1 Major Histocompatibility Complex (MHC) and T Cell Receptors

2 Historical Background Genes in the MHC were first identified as being important genes in rejection of transplanted tissues Genes within the MHC were highly polymorphic Studies with inbred strains of mice showed that genes within the MHC were also involved in controlling both humoral and cell-mediated immune responses Responder/Non-responder strains

3 Historical Background There were three kinds of molecules encoded by the MHC Class I Class II Class III Class I MHC molecules are found on all nucleated cells (not RBCs) Class II MHC molecules are found on APC Dendritic cells, Macrophages, B cells, other cells

4 Historical Background Nucleated cells Class I MHC Class II MHC APCs RBCs

5 Historical Background Class III MHC molecules Some complement components Transporter proteins

6 Historical Background It was not until the discovery of how the TCR recognizes antigen that the role of MHC genes in immune responses was understood TCR recognizes antigenic peptides in association with MHC molecules T cells recognize portions of protein antigens that are bound non-covalently to MHC gene products Tc cells recognize peptides bound to class I MHC molecules Th cells recognize peptides bound to class II MHC molecules

7 Historical Background Three dimensional structures of MHC molecules and the TCR have been determined by X-ray crystallography

8 Structure of Class I MHC Two polypeptide chains, a long α chain and a short β (β2 microglobulin) Four regions Cytoplasmic region containing sites for phosporylation and binding to cytoskeletal elements Transmembrane region containing hydrophobic amino acids

9 Structure of Class I MHC Four regions A highly conserved α3 domain to which CD8 binds A highly polymorphic peptide binding region formed from the α1 and α2 domains Β2-microglobulin helps stabilize the conformation

10 Structure of Class I MHC Variability map of Class 1 MHC α Chain

11 Structure of Class I MHC Ag-Binding Groove Groove composed of an α helix on two opposite walls and eight β-pleated sheets forming the floor Residues lining the groove are most polymorphic Groove accomodates peptides of 8-10 amino acids long From Janeway et al., Immunobiology 6 th Ed.

12 Structure of Class I MHC Specific amino acids on peptide required for anchor site in groove Many peptides can bind Vaccine development Ag Binding Groove From Janeway et al., Immunobiology 6 th Ed.

13 Class I polymorphism Number of alleles Locus (allotypes) HLA - A 218 HLA - B 439 HLA - C 96 There are also HLA - E, HLA - F and HLA - G Relatively few alleles

14 Structure of Class II MHC Two polypeptide chains,α and β, of roughly equal length Four regions Cytoplasmic region containing sites for phosporylation and binding to cytoskeletal elements

15 Structure of Class II MHC Four regions Transmembrane region containing hydrophobic amino acids A highly conserved α2 and a highly conserved β2 domains to which CD4 binds A highly polymorphic peptide binding region formed from the α1 and β1 domains

16 Structure of Class II MHC Variability map of Class2 MHC β Chain

17 Structure of Class I MHC Ag-Binding Groove Groove composed of an α helix on two opposite walls and eight β-pleated sheets forming the floor Both the α1 and β1 domains make up the groove Residues lining the groove are most polymorphic From Janeway et al., Immunobiology 6 th Ed.

18 Structure of Class I MHC Ag-Binding Groove Groove is open and accomodates peptides of amino acids long, some of which are ouside of the groove Anchor site rules apply From Janeway et al., Immunobiology 6 th Ed.

19 Class II polymorphism Locus Number of alleles (allotypes) HLA - DP A 12 HLA - DP B 88 HLA - DQ A 17 HLA - DQ B 42 HLA - DR A HLA - DR B1 HLA DR B3 HLA DR B4 HLA DR B There are also HLA - DM and HLA - DO Relatively few alleles

20 Important Aspects of MHC Although there is a high degree of polymorphism for a species, an individual has maximum of six different class I MHC products and only slightly more class II MHC products (considering only the major loci). Each MHC molecule has only one binding site. The different peptides a given MHC molecule can bind all bind to the same site, but only one at a time.

21 Important Aspects of MHC Because each MHC molecule can bind many different peptides, binding is termed degenerate. MHC polymorphism is determined only in the germline. There are no recombinational mechanisms for generating diversity. MHC molecules are membrane-bound; recognition by T cells requires cell-cell contact.

22 Important Aspects of MHC Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell. A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control.

23 Important Aspects of MHC Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. This is the second level of control. Cytokines (especially interferon-γ) increase level of expression of MHC.

24 Important Aspects of MHC Peptides from the cytosol associate with class I MHC and are recognized by Tc cells. Peptides from within vesicles associate with class II MHC and are recognized by Th cells. Why so much polymorphism? Survival of the species

25 Structure of the T cell Receptor Heterodimer with one α and one β chain of roughly equal length A short cytoplamic tail not capable of transducing an activation signal A transmembrane region with hydrophobic amino acids

26 Structure of the T cell Receptor Both α and β chains have a variable (V) and constant (C) region V regions of the α and β chains contain hypervariable regions that determine the specificity for antigen

27 Structure of the T cell Receptor Each T cell bears TCRs of only one specificity (allelic exclusion)

28 Genetic Basis for Receptor Generation Generation of a vast array of BCRs is accomplished by recombination of various V, D and J gene segments encoded in the germline Generation of a vast array of TCRs is accomplished by similar mechanisms TCR β chain genes have V, D and J gene segments TCR α chain genes have V and J gene segments

29 Organization and Rearrangement of the T Cell Receptor Germline ß-Chain Gene L Vß1 L Vß2 L Vßn Dß 1 Jß Jß 1 6 Cß 1 Dß 2 Jß Jß 1 7 Cß 2 P P P D-J rearrangement E L Vß1 L Vß2 L Vßn Dß 1 Jß 1 5 Cß 1 Dß 2 Jß Jß 1 7 Cß 2 P P P E DNA V-D rearrangement L Vß1 L Vß2 Dß 1 Jß 1 5 Cß 1 Dß 2 Jß Jß 1 7 Cß 2 P P E DNA Transcription Vß2 Dß 1 Jß 1 5 Cß 1 RNA

30 Comparison of TCR and BCR Property BCR (sig) TCR Genes Many VDJs, Few Cs Yes Yes VDJ rearrangement Yes Yes V regions generate Ag-binding site Yes Yes Allelic exclusion Yes Yes Somatic mutation Yes No Proteins Transmembrane form Yes Yes Secreted form Yes No Isotypes with different functions Yes No Valence 2 1

31 γδ TCR Small population of T cells express a TCR that contain γ and δ chains instead of α and β chains The Gamma/Delta T cells predominate in the mucosal epithelia and have a repertoire biased toward certain bacterial and viral antigens Genes for the δ chains have V, D and J gene segments; γ chains have V and J gene segments Repertoire is limited

32 γδ TCR Gamma/Delta T cells can recognize antigen in an MHC-independent manner Gamma/Delta T cells play a role in responses to certain viral and bacerial pathogens

33 TCR and CD3 Complex TCR is closely associated with a group of 5 proteins collectively called the CD3 complex γ chain δ chain 2 ε chains 2 ξ chains CD3 proteins are invariant

34 Role of CD3 Complex CD3 complex necessary for cell surface expression of TCR during T cell development CD3 complex transduces signals to the interior of the cells following interaction of Ag with the TCR

35 The Immunological Synapse The interaction between the TCR and MHC molecules are not strong Accessory molecules stabilize the interaction CD4/Class II MHC or CD8/Class I MHC CD2/LFA-3 LFA-1/ICAM-1

36 The Immunological Synapse Specificity for antigen resides solely in the TCR The accessory molecules are invariant Expression is increased in response to cytokines

37 The Immunological Synapse Engagement of TCR and Ag/MHC is one signal needed for activation of T cells Second signal comes from costimulatory molecules CD28 on T cells interacting with B7-1 (CD80) or B7-2 (CD86) Others Costimulatory molecules are invariant Immunological synapse

38 Costimulation is Necessary for T Cell Activation Engagement of TCR and Ag/MHC in the absence of costimulation can lead to anergy Engagement of costimulatory molecules in the absenece of TCR engagement results in no response Activation only occurs when both TCR and costimulatory molecules are engaged with their respective ligands Downregulation occurs if CTLA-4 interacts with B7 CTLA-4 send inhibitory signal

39 Key Steps in T cell Activation APC must process and present peptides to T cells T cells must receive a costimulatory signal Usually from CD28/B7 Accessory adhesion molecules help to stabilize binding of T cell and APC CD4/MHC-class II or CD8/MHC class I LFA-1/ICAM-1 CD2/LFA-3 Signal from cell surface is transmitted to nucleus Second messengers Cytokines produced to help drive cell division IL-2 and others

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