Antigen Recognition by T cells

Transcription

1 Antigen Recognition by T cells TCR only recognize foreign Ags displayed on cell surface These Ags can derive from pathogens, which replicate within cells or from pathogens or their products that cells have internalized by endocytosis Foreign peptides are delivered to cell surface by major histocompatibility complex (MHC) TCR TCR

2 Antigen Recognition by T cells The T-cell receptor is very similar to Fab fragment of immunoglobulin Binding sites Secretion BCR 2 Yes TCR 1 No

3 The T-cell receptor (TCR) resembles a membrane-bound Fab Similarities The TCR & the Fab are both heterodimers in which the 2 chains are disulfide linked to each other & each has a single V & single C region

4 Structure of the TCR

5 The crystal structure of an TCR

6 Antigen Recognition by T cells A TCR recognize Ag in the form of a complex of a foreign peptide bound to MHC molecule Ag recognition by B cells involves direct binding of Ig to intact Ag Ligand recognized by T cells is a complex of peptide and MHC molecule

7 Differences in the epitopes of HEL that are bound by immunoglobulin & by a TCR Three B-cell epitopes of HEL occur on the surface of the protein T-cell epitopes of HEL can occur anywhere in the protein (surface or internally) because they are broken into peptides and presented by MHC Ligand recognized by T cell is a complex of peptide and MHC molecule

8 Antigen Recognition by T cells There are 2 classes of MHC molecules with distinct subunit composition but similar 3- dimensional structures

9 The structure of an MHC class I molecule

10 The structure of an MHC class II molecule

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12 Models of peptides bound to MHC peptide binding sites MHC class I MHC class II

13 Antigen Recognition by T cells Peptides are stably bound to MHC molecules and also serve to stabilize MHC molecule on cell surface Unlike other peptide-binding receptors, which usually bind only single type of peptide, MHC molecules are able to bind to many different peptides MHC molecules are unstable when peptides are not bound

14 Antigen Recognition by T cells MHC class I molecules bind short peptides of 8-10 amino acids by both ends Free amino and carboxy termini of peptide bind to invariant sites that are found at each end of cleft of MHC class I molecules Peptides that bind to MHC I are 8-10 amino acids long Variations in peptide length are accommodated by kinking in peptide backbone MHCs are highly polymorphic (hundreds of alleles) and each individual carries only a small selection of them

15 The terminal amino acids of a peptide contact the peptidebinding site of a MHC class I molecule

16 Peptides bind to MHC class I molecules via structurally similar anchor residues

17 Antigen Recognition by T cells The length of peptides bound by MHC class II molecules is not constrained Peptide backbone bind to side chains of conserved amino acids in peptide-binding cleft of MHC class II molecules Peptides that bind to MHC II are at least 13 amino acids long (13-17 aa)

18 Amino acid residue along the length of a peptide form contacts with MHC class II molecule residues in the peptide binding site

19 Peptides that bind MHC class II molecules are variable in length & their anchor residues lie at various distances from the ends of the peptide

20 Antigen Recognition by T cells The crystal structures of several peptide:mhc:t-cell receptor complexes show a similar T-cell receptor orientation over the peptide:mhc complex

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23 Antigen Recognition by T cells The CD4 and CD8 cell-surface proteins of T cells are required to make an effective response to antigen

24 Antigen Recognition by T cells CD4 T cells & CD8 T cells MHC class I & MHC class II CD4 binds to MHC class II and CD8 to MHC class I CD4 & CD8 bind Lck and bring it into close to TCR When CD4 and TCR or CD8 and TCR can simultaneously bind to the same MHC:peptide complex, sensitivity of T cell to Ag presented by MHC is increased by 100 folds

25 Structures of the CD4 & CD8 co-receptors for the TCR

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27 TCR & CD8 bind to different MHC class I domains TCR MHC class I CD8

28 Antigen Recognition by T cells Two classes of MHC molecule are expressed differentially on cells MHC class I is expressed in all nucleated cells MHC class I present peptides from viruses to CD8 cytotoxic T cells, which are specialized to kill cell that they specifically recognize MHC class II is normally expressed in B, DC, macrophage MHC class II present peptides from pathogens internalized by endocytosis to CD4 T cells, which stimulate B cells or macrophages Cytokines, especially IFN-, increases MHC expression

29 The two types of MHC molecules do not have the same distribution on the various cell types of the body

30 Antigen Recognition by T cells A distinct subset of T cells bears alternative receptor made up of and chains A minority population of T cells bear TCR TCRs bind heat-shock proteins and non-peptide ligands such as phosphorylated ligands or mycobacterial lipid antigens TCRs are not restricted by MHC class I and II TCR bind free Ag and peptides presented by nonclassical MHC-like molecules

31 Comparison of the structures of the & TCRs