chapter 6 antigen presentation to t lymphocytescontents.kocw.net/kocw/document/2013/gacheon/... ·...

Chapter 6

Antigen Presentation to

T lymphocytes

Function of MHC molecules is to bind peptide fragments derived from pathogens and display them on cell surface for recognization by appropriate T cells MHC is polygenic: MHC class I - HLA-A, B, C MHC class II - HLA-DP, DQ, DR MHC is highly polymorphic: HLA-A1~414

Major Histocompatibility Complex (MHC) and Its Functions

Many proteins involved in Ag processing and presentation are encoded by genes within MHC

MHC is located on chromosome 6 in humans, 17 in mouse

Human leukocyte antigen (HLA), H-2 (mouse)

MHC class I – HLA-A, -B, -C

MHC class II – HLA-DR, -DP, DQ

When cells are treated with IFN, expression of MHC class I, proteasome, tapasin and TAP genes is increased

Expression of classical MHC class II, Ii, DM, DO is induced by IFN- via tanscriptional activator, MHC class II transactivator (CIITA)

MHC and Its Functions

Highly simplified maps of the human & mouse MHC

Protein products of MHC class I and class II genes are highly polymorphic

Because of polygeny of MHC, every person will express at least 3 different Ag-presenting MHC class I and 3 or 4 MHC class II on the cells

Number of different MHC expressed on the cells of most people is greater because of extreme polymorphism of MHC and codominant expression of MHC

Most individuals will be heterozygous at MHC loci because each allele is present at high frequency in population


Protein products of MHC class I and class II genes are highly polymorphic

Expression of MHC alleles is codominant, with protein products of both alleles at a locus being expressed in the cell

With 3 MHC class I genes and 4 MHC class II genes human typically expresses 6 different MHC class I and 8 different MHC class II on the cells

For MHC class II genes, number of different MHC may be increased further by combination of and chains encoded by different chromosomes


Human MHC genes are highly polymorphic

Expression of MHC is co-dominant

The combination of numerous MHC

genes & of numerous allelic variants of each

MHC gene together increase the diversity of

antigenic peptides presented to T

cells

A

C

B

12

31

A7

A22 C4

C16 B11 B34

Some new alleles arise by point mutations and others by gene conversion

MHC polymorphism affects Ag recognition by T cells by influencing both peptide binding and contacts between TCR and MHC molecule

Most of differences of individual MHC alleles are localized to peptide-binding groove

Polymorphic residues that line peptide-binding groove determine peptide-binding properties of different MHC

When processing of protein do not generate any peptides with a suitable motif for binding to any of MHC, individual fails to respond to Ag



Such failures in responsiveness to simple Ags were first reported in inbred animals, where they were called immune response (Ir) gene defects

Ir gene defects are common in inbred strains of mice because mice are homozygous at all their MHC loci and thus, express only one type of MHC from each gene locus

This limits range of peptides they can present to T cells

MHC polymorphism guarantees a sufficient number of different MHC in a single individual to make this type of nonresponsiveness unlikely



When mice are infected with a virus, they generate cytotoxic T cells that kill self cells infected with virus, while sparing uninfected cells or cells infected unrelated viruses

Cytotoxic T cells induced by viral infection in mice of MHC genotype a (MHCa) would kill any MHCa cell infected with that virus but would not kill cells of MHC genotype b or c or d, even if they were infected with the same virus

Because MHC genotype restricts Ag specificity of T cells, this effect is called MHC restriction, which is a critical feature of Ag recognition by all functional classes of T cells


Genetic recombination as a source of diversity in MHC genes

MHC restriction of T-cell recognition of antigenic peptide means that an antigenic peptide can be bound by a TCR

only when it is presented by a “self” MHC molecule

Alloreactive T cells recognizing nonself MHC molecules are very abundant Discovery of MHC restriction explain recognition of nonself MHC in rejection of organs and tissue transplanted between members of the same species

Transplanted organs from donors bearing MHC that differ from those of recipient are invariably rejected

Rapid and very potent cell-mediated immune response to transplant results from presence in any individual of large numbers of T cells that are specifically reactive to nonself or allogeneic MHC molecules

Mixed lymphocyte reaction (MLR) – reaction that occur when T cells from one individual are mixed with lymphocytes from a second individual

Alloreactive T cells recognizing nonself MHC molecules are very abundant

If T cells of an individual recognize the other individual’s MHC as foreign, T cells will proliferate

1-10% of all T cells in an individual will respond to stimulation by cell from another (alloreaction)

There are 2 ways in which TCR may bind to nonself MHC

- Peptide-dominant binding – peptide bound by nonself MHC interacts strongly with TCR and T cells bearing this TCR are stimulated to respond (cross-reactive recognition)

- MHC-dominant binding – alloreactive T cells respond because of direct binding of TCR to distinctive features of nonself MHC

Many T cells respond to superantigens

SuperAgs are distinct class of Ag that are produced by many different pathogens and stimulate a primary T cell response similar in magnitude to a response to allogeneic MHC molecules

SuperAgs have a distinct mode of binding to both MHC and TCR that enables them to stimulate very large numbers of T cells (2-20% of all T cells)

SuperAgs are unlike other protein Ags, in that they are recognized by T cells without being processed into peptides that are captured by MHC

SuperAgs as intact protein bind to outside surface of MHC class II that has already bound peptide and many TCR


Many T cells respond to superantigens

This mode of stimulation does not prime an adaptive immune response specific for pathogens

Instead, it causes a massive production of cytokine by CD4 T cells

These cytokines have 2 effects on host: systemic toxicity and suppression of adaptive immune response

Bacterial superAgs: staphylococcal enterotoxins (Ses) and toxic shock syndrome toxin-1 (TSST-1)


Superantigens bind directly to both TCR and MHC class II, but binding is outside of the peptide binding site

Superantigen activates T cells in a polyclonal manner

Molecular model of Staphylococcal superantigen binding to TCR and MHC class II

Because superantigens bind MHC class II & TCR independently of the TCR specificity & of the peptide being presented, T cells are activated in an antigen-independent manner and numerous T cells of differing specificity are activated

MHC polymorphism extends range of Ags to which immune system can respond

Extensive polymorphism of MHC proteins has almost certainly evolved to outflank evasive strategies of pathogens

Requirement that pathogen Ags must be presented by MHC provides 2 possible ways of evading detection

- One is through mutations that eliminate from pathogen’s proteins all peptides able to bind MHC molecules

- The other is blockade of presentation of their peptides by MHC and thus pathogens can avoid adaptive immune response


A variety of genes with specialized functions in immunity are also encoded in MHC

MHC class IB, nonclassical MHC – mouse MHC class IB, H2-M3 can present peptides with N-formylated amino termini, which is of interest because all bacteria initiate protein synthesis with N-formylmethionine

Cells infected with cytosolic bacteria can be killed by CD8 T cells that recognize N-formylated bacterial peptides bound to H2M3

The other genes that map within MHC include genes encoding complement components, cytokines (MHC class III)

Many studies revealed associations between susceptibility to certain diseases and particular alleles of MHC genes


Specialized MHC class I molecules act as ligands for activation and inhibition of NK cells

Some class IB such as MIC (MICA/MICB) are induced in response to cellular stress such as heat shock

MICA/MICB are expressed in fibroblast and epithelial cells, particularly in intestinal epithelial cells and may have a role in innate immunity or induction of immune responses in circumstances in which IFN are not produced

MICA/MICB are recognized by a receptor that is present on NK, T cells and some CD8 T cells and can activate these cells to kill MIC-expressing targets

MIC receptor is composed of two chains, NKG2D and DAP10



UL16-binding proteins, ULBP bind NKG2D and can co-stimulate NK, T cells and some CD8 T cells

Other MHC class IB such as HLA-G inhibit cell killing by NK cells

HLA-G is expressed on fetus-derived placental cells that express no classical MHC class I and cannot be recognized by CD8 T cells but, unlike other cells lacking classical MHC class I, they are not killed by NK cells

This seems to be because HLA-G is recognized by an inhibitory receptor, ILT2, on NK cell, which prevents NK cell from killing placental cells



NK activating ligands and receptors

MICA, MICB, ULBP – NKG2D, DAP10

NK inhibitory ligands and receptors

HLA-G, HLA-E – ILT2, NKG2A


The CD1 family of MHC class I-like molecules is encoded outside the MHC and presents microbial lipids to CD1-restricted T cells

MHC class I-like genes, CD1 is expressed on DC and monocytes as well as some thymocytes

CD1 molecules can present Ags to T cells

CD1 behaves like an MHC class II molecule

CD1 can bind and present glycolipid

T cells that recognize lipids presented by CD1 molecules express neither CD4 nor CD8


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