Antigen Presentation to T lymphocytes

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1 Antigen Presentation to T lymphocytes Immunology 441 Lectures 6 & 7 Chapter 6 October 10 & 12, 2016 Jessica Hamerman Office hours by arrangement

2 Antigen processing: How are the peptides bound by MHC molecules generated? Antigen presentation: How do the peptides bind to MHC molecules and get delivered to the cell surface to be recognized by T cells? MHC genes and polymorphism: How does this ensure our T cells can respond to a wide variety of pathogens?

3 The Major Histocompatibility Complex and its functions

4 How do you ensure a good T cell response to a pathogen? 1. You must have a T cell receptor specific for a peptide derived from that pathogen. 2. You must have an MHC molecule that binds with high affinity to peptides from the pathogen to present to T cells. Two unique features of the MHC ensure they can bind a wide variety of peptides--it is polygenic and polymorphic

5 MHC genes Polygenic--several genes encoding a family of related proteins Polymorphic--there are multiple alleles of each gene (most genes have very few alleles)

6 Genetic organization of the MHC A cluster of closely linked genes consisting of more than 200 genes and extending over at least 4 million base pairs. Encodes MHC molecules and other genes involved in Ag processing and presentation (but not β2m or Ii) Chrom 6 =Human leukocyte antigen MHC molecules are polygenic HUMAN 3 MHC class I 3 MHC class II Chrom 17 MOUSE 3 MHC class I 2 MHC class II

7 Genetic organization of the Human MHC MHC II Non-MHC immune genes MHC I MIC Pseudogenes

8 The MHC genes are the most polymorphic in our genome # alleles Chrom 6 Chrom 17 Each MHC allele is expressed frequently in the population, so most people express 2 different alleles of each MHC gene (heterozygous) A combination of MHC alleles on one chromosome which are inherited together (because the genes are closely linked) is a haplotype

9 Expression of MHC genes is codominant Most individuals are heterozygous at each locus MHC expression is codominant (the gene from each chromosome is expressed) Even siblings only have a 1 in 4 chance of expressing the exact same MHC on their cells--making it hard to find MHC-matched donors for tissue transplantation Chrom 6 Chrom 17

10 Both polymorphism and polygeny contribute to the diversity of MHC molecules expressed by an individual Chrom 6 Chrom 17

11 Pairing of MHC class II proteins from different chromosomes increases the potential number of MHC molecules expressed MHC Class I Molecules B a Bb C a C b A a Maternal MHC A b MHC class I: 3 genes x 2 alleles = 6 different MHC I proteins DRα a β a MHC Class II Molecules DRα b β b DRα a β b DPα a β a DPα b β b DRα b β a DQα a β a DRα a β a B a C a A a DQα b β b DRα b β b B b C b A b Paternal MHC DQα b β a DQα a β b DQα a β a DQα b β b MHC class II: 3 genes x 2 alleles x 2 (pairing of α and β genes from different chromosomes) = 12 different MHC II proteins

12 How did the polymorphism in MHC genes arise? New alleles arise by point mutation and gene conversion Polymorphism has been selected for in MHC genes This can be seen by the greater number of mutations leading to amino acid substitutions compared to silent mutations (that do not cause amino acid change) than would be expected by chance

13 How does having so many different MHC molecules ensure that we will have productive T cells responses against most pathogens?

14 Allelic variations in MHC occur in the peptide binding pocket Thus, different MHC alleles bind different pathogen-derived peptides. There is diversity in antigen presentation, not just in antigen recognition (T cell receptor).

15 Peptide binding is defined by anchor residues MHC Class I Binds 8-10 aa peptides Green anchor residues define the peptide-binding motif of peptides N and C-termini contribute to binding Each MHC molecule can bind many peptides, as long as they have the appropriate anchor residues

16 Peptide binding is defined by anchor residues MHC Class II Binds peptides 13 aa or longer Green anchor residues define the peptide-binding motif of peptides N and C-termini do not contribute to binding and extend past the end of the peptide-binding groove

17 Different MHC proteins have different anchor residues and therefore bind different peptides * * * *

18 How does having so many different MHC molecules ensure that we will have productive T cells responses against most pathogens? Each MHC protein has a different peptide binding specificity. Because the MHC molecules are polygenic and polymorphic, each person expresses a diverse set of MHC proteins that can bind a wide array of peptides, increasing the likelihood that every pathogen (and every protein) will have at least one peptide bound by an MHC molecule. What happens if a protein has no peptides that bind an individual s MHC?

19 MHC restriction--the TCR recognizes foreign antigen only when bound to MHC How did immunologists figure this out? First, it was discovered that immune responses to certain foreign proteins could occur in some inbred strains of mice, but not others--this was mapped genetically to the Immune response (Ir) genes, later found to be the MHC region genotype that controlled this response Later, it was found that T cells from certain strains of mice could only respond to antigen presenting cells from the same strain of mouse--again mapping to the MHC, so now it was known the Ir genes controlled T cell responses

20 MHC restriction--the TCR recognizes foreign antigen only when bound to MHC

21 MHC restriction--the TCR recognizes foreign antigen only when bound to MHC Doherty and Zinkernagel, 1974 Nobel Prize, 1996

22 The TCR binds both peptide and MHC TCR peptide MHC

23 The TCR binds both peptide and MHC

24 Allelic variations in MHC occur in the peptide binding pocket and in TCR contact residues

25 Selective pressure between pathogens and MHC The fact that the MHC is polymorphic and polygenic allows for most individuals to present peptides from most pathogens to T cells A pathogen could mutate its proteins so no peptides could be presented--but this is difficult due to the many MHC proteins present in each person

26 Selective pressure between pathogens and MHC The fact that the MHC is polymorphic and polygenic allows for most individuals to present peptides from most pathogens to T cells A pathogen could mutate its proteins so no peptides could be presented--but this is difficult due to the many MHC proteins present in each person EBV and HLA-A11 in SE Asia and Papua New Guinea

27 Selective pressure between pathogens and MHC The fact that the MHC is polymorphic and polygenic allows for most individuals to present peptides from most pathogens to T cells A pathogen could mutate its proteins so no peptides could be presented--but this is difficult due to the many MHC proteins present in each person HLA-A11 Frequency HLA-A11 has a high allele frequency in SE Asia and Papua New Guinea, thus many people are homozygous for HLA-A11 EBV has exploited this to mutate key amino acids only in these geographic areas de Campos-Lima, 1994, J. Exp. Med.,179:1297

28 Selective pressure between pathogens and MHC The fact that the MHC is polymorphic and polygenic allows for most individuals to present peptides from most pathogens to T cells A pathogen could mutate its proteins so no peptides could be presented--but this is difficult due to the many MHC proteins present in each person HLA-A11 Frequency Anchor residues for HLA-A11 de Campos-Lima, 1994, J. Exp. Med.,179:1297

29 Selective pressure between pathogens and MHC MHC alleles that are protective can also be selected for in populations due to evolutionary pressure from pathogens. The HLA-B53 allele is associated with recovery from severe malaria and is very common in West Africa, where malaria is endemic, but is rare elsewhere. Malaria risk HLA-B53

30 Selective pressure between pathogens and MHC Pathogens may also attempt to evade T cell responses by blocking antigen processing and presentation with immunoevasins The immune system has evolved a mechanism for detecting these cells missing MHC on their surface by Natural Killer (NK) cells NK cells are a type of lymphocyte that does not have a rearranged antigen receptor (unlike T and B cells)

31 Natural Killer cells kill cells that are lacking MHC class I and are infected Healthy cell NK Infected cell NK Normal, healthy cells express MHC Class I ligands for NK inhibitory receptors and are not killed by NK cells. Some virally-infected cells have reduced levels of class I MHC on their surface and also express ligands for NK cell activating receptors. These cells that can escape CD8 T cell detection are killed by NK cells. NK cells are also important in early control of viral infection.

32 MHC Class Ib genes Some of these so-called non-classical MHC class I molecules are encoded in the MHC Chrom 6 Chrom 17

33 MHC Class Ib genes Some of these so-called non-classical MHC class I molecules are encoded in the MHC Some are recognized by natural killer activating and inhibitory receptors (HLA-E/Qa-1, HLA-G, MICA/B, ULBP) Some present specialized molecules that can t bind classical MHC H2-M3 in mouse binds peptides with N-terminal formylmethionine (only found in the mitochondria and in bacteria) CD1 molecules have a very hydrophobic binding groove specialized for presentation of non-peptide, glycolipid antigens to T cells. These glycolipids can be from self or from bacterial pathogens. CD1 molecules have their own unique antigen processing and presentation pathway. Some are recognized by γδ T cells (mouse T22 and T10)

34 Antigen processing and presentation to T cells ensures productive responses to pathogens

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