Talk 5Talk 5

TT 细胞受体与主要组织相容性细胞受体与主要组织相容性复合体分子复合体分子

T-Cell Receptor and Major HistocompatiT-Cell Receptor and Major Histocompatibility Complex Moleculesbility Complex Molecules

OverviewOverviewT cells recognize antigens that are presented by antigen presenting T cells recognize antigens that are presented by antigen presenting cells (APCs) onlycells (APCs) only

The way which TCR recognizes antigens is quite different from antThe way which TCR recognizes antigens is quite different from antigen recognition by antibody (igen recognition by antibody (e.ge.g. recognize antigen fragments pres. recognize antigen fragments presented by MHC molecules only)ented by MHC molecules only)

The most important antigen-presenting molecules are class I and clThe most important antigen-presenting molecules are class I and class II molecules of MHC, and more recently other antigen-presentiass II molecules of MHC, and more recently other antigen-presenting molecules have been identified (ng molecules have been identified (e.ge.g. CD1 presents lipid and glyc. CD1 presents lipid and glycolipid antigens)olipid antigens)

However, antibody and TCR have many similarities, they are structHowever, antibody and TCR have many similarities, they are structurally related (folded into Ig superfamily domains), clonally distriburally related (folded into Ig superfamily domains), clonally distributed (each has a receptor with individual specificity) and their receuted (each has a receptor with individual specificity) and their receptors are generated by somatic recombination ptors are generated by somatic recombination (( 体细胞重组体细胞重组 )) from from a limited number of germ line a limited number of germ line (( 生殖系生殖系 )) genes genes

TCR:CD3 ComplexTCR:CD3 ComplexThe The TCR heterodimer TCR heterodimer forms the recognition unit forms the recognition unit of the receptorof the receptor

The CD3 complex associaThe CD3 complex associates with the tes with the or or γδγδforms forms of TCRof TCR

The The γδγδTCR structurally reTCR structurally resemble the semble the TCRTCR

The external portion of eaThe external portion of each chain consists of two dch chain consists of two domains, resembling Ig variomains, resembling Ig variable and constant domainsable and constant domains

TCR Gene and ExpressionTCR Gene and ExpressionThe organization of the gene seThe organization of the gene segments for TCR gments for TCR and and chains chains is generally homologous to the is generally homologous to the L chain and H chain of Ig gene L chain and H chain of Ig gene segments, respectivelysegments, respectively

Like Ig genes in B cells, TCR gene segments rearrange during development to form complete V-domain exons

The process takes place in the thymus

TCR serves only for antigen recognition and its constant region genes are much simpler

Number and Diversity between TCR and Number and Diversity between TCR and Ig Gene SegmentsIg Gene Segments

TCR diversity is focused in CDR3. Somatic hypermutation is not a major mechanism for generating diversity in TCR

Major Histocompatibility Complex MoleculesMajor Histocompatibility Complex Molecules

The gene complex was first identified based on the ability of a The gene complex was first identified based on the ability of a donor to accept grafts from the recipient sharing the same MHC donor to accept grafts from the recipient sharing the same MHC hapotypehapotype

MHC contains >100 gene lociMHC contains >100 gene loci,, but only class I and class II mol but only class I and class II molecules determine graft rejection and present antigensecules determine graft rejection and present antigens

MHC class I and II molecules are highly polymorphic cell-surfaMHC class I and II molecules are highly polymorphic cell-surface glycoproteinsce glycoproteins

The gene complex in mouse is called H-2 and in human leukocThe gene complex in mouse is called H-2 and in human leukocyte antigen (HLA) systemyte antigen (HLA) system

The remaining genes in MHC are very diverse, including genes The remaining genes in MHC are very diverse, including genes coding for complement components (C4, C2 and factor B), cytcoding for complement components (C4, C2 and factor B), cytokines, enzymes, heat-shock proteins and other molecules involokines, enzymes, heat-shock proteins and other molecules involved n antigen processing, which are collectively called class III ved n antigen processing, which are collectively called class III genes genes

Overall Organization of MHCOverall Organization of MHC

• Three human class I loci, two or three mouse class I loci;

• Human class II genes are located in the HLA-D region, while murine class II genes are located in the H-2I region

MHC Class I MoleculesMHC Class I Molecules

Consist of an MHC-encoded Consist of an MHC-encoded heavy chain bound toheavy chain bound toββ22-micr-micr

oglobulinoglobulin

ββ22-microglobulin is essential -microglobulin is essential

for expression of MHC class for expression of MHC class I moleculesI molecules

Heavy chain Heavy chain αα1 and 1 and αα2 doma2 domains form the antigen-binding ins form the antigen-binding groovegroove

Variations in amino acid seqVariations in amino acid sequence change the shape of thuence change the shape of the binding groovee binding groove

MHC Class II MoleculesMHC Class II Molecules

The overall structure resembles class I molecules

T cells recognize the T cells recognize the appropriate MHC molecule appropriate MHC molecule bound-peptides onlybound-peptides only

In a MHC class I molecule, In a MHC class I molecule, the bound peptide is the bound peptide is surrounded by the two surrounded by the two helices from helices from 1 and 1 and 2 2 domains domains

In a MHC class II In a MHC class II molecule, the peptide is molecule, the peptide is held between the held between the helices helices of the of the 1 and 1 and 1 domains1 domains

Interactions of MHC Molecules with Interactions of MHC Molecules with Antigenic PeptidesAntigenic Peptides

Interactions of MHC Molecules with Interactions of MHC Molecules with Antigenic PeptidesAntigenic Peptides

MHC class II binding groove accommodates longer peptides MHC class II binding groove accommodates longer peptides than class Ithan class I

Peptides are held in the binding cleft by characteristic anchor Peptides are held in the binding cleft by characteristic anchor residuesresidues

The length of Peptides Bound by MHC The length of Peptides Bound by MHC Class II MoleculesClass II Molecules

The peptide lies in an extended The peptide lies in an extended conformation along the conformation along the peptide-binding groovepeptide-binding groove

In principle, no upper limit on In principle, no upper limit on the length of peptides binding the length of peptides binding to the molecules, but longer to the molecules, but longer peptides are trimmed by peptides are trimmed by peptidases to 13-17 amino peptidases to 13-17 amino acids in most casesacids in most cases

Amino acid side chains at Amino acid side chains at residues 1, 4, 6, and 9 of a residues 1, 4, 6, and 9 of a minimal MHC class II-bound minimal MHC class II-bound peptide are held in the binding peptide are held in the binding pocketspockets

It is more difficult to detect a peIt is more difficult to detect a peptide-binding motif for MHC clptide-binding motif for MHC class II moleculesass II molecules

MHC Polymorphism Affects Antigen MHC Polymorphism Affects Antigen RecognitionRecognition

Individual MHC molecules can differ by up to 20 amino acids

Most of the differences are on the surfaces of the outer domain, the peptide-binding groove in particular

Different allelic variants of MHC molecules bind different peptides

Previously called immune response (Ir) gene encodes MHC class II molecules

• Polymorphism of MHC molecules guarantees sufficient MHC molecules to avoid non-responsiveness

Distribution of MHC MoleculesDistribution of MHC Molecules

TissueTissue MHC IMHC I MHC IIMHC II

Lymphoid Lymphoid tissuetissue

T cellT cell

B cellB cell

MacrophageMacrophage

Other APCOther APC

++++++

++++++

++++++

++++++

++

++++++

++++

++++++

Other cellsOther cells

NeutrophilNeutrophil

LiverLiver

KidneyKidney

BrainBrain

++++++

++

++

++

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——

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——

Different distribution of MHC molecules reflects the functions of T cells

Class I molecules present intracellular antigenic peptides to CD8+Tc cells， inducing cellular immune response (CTL)

The main function of CD4+ T cells is to activate other effecter cells and thus MHC class II molecules are present mainly on APC

The expression levels of MHC molecule influence activation of T cells

Interaction of TCR with MHC-Interaction of TCR with MHC-Bound AntigensBound Antigens

Aggregation of TCRs iAggregation of TCRs initiates T-cell activationitiates T-cell activationn

Antigenic peptides can Antigenic peptides can induce or antagonize induce or antagonize T-cell activationT-cell activation

CD4 and CD8 are co-rCD4 and CD8 are co-receptors of TCReceptors of TCR

APC

T

CD8/4

MHC I/II

TCR

MHC RestrictionMHC Restriction

A T cell specific for MHCA T cell specific for MHCaa-pept-peptideidexx will not recognize MHC will not recognize MHCbb-p-peptideeptidexx or MHC or MHCaa-- antigenantigenyy

Co-recognition of peptide and Co-recognition of peptide and MHC molecule is known as MMHC molecule is known as MHC restriction (the MHC molecHC restriction (the MHC molecules restrict the ability of the T ules restrict the ability of the T cell to recognize antigen)cell to recognize antigen)

The restriction may result from The restriction may result from direct contact between MHC mdirect contact between MHC molecule and TCR or indirect effolecule and TCR or indirect effect of MHC polymorphism on tect of MHC polymorphism on the peptideshe peptides