chapter 5: antigen recognition by T lymphocytes

test 3

how are t-cell and b-cell receptors similar?

structurally

• membrane bound to glycoprotein

• belong to immunoglobulin superfamily

• gene organized as non-functional segments

• functional genes produced through somatic recombination to generate diversity and specificity

what is the common function of t-cells and b-cells?

to recognize antigens and develop an immune response

what to b-cells recognize?

intact antigens; proteins, carbohydrates, and lipids present on the surface of pathogens or their toxins

what do t-cells recognize?

peptide antigens present on antigen presenting cells

TCR

t-cell receptor

TCR interacts with what?

antigen presenting glycoproteins called MHC. these molecules are expressed on antigen presenting cells (APCs)

t-cell receptor resembles what?

a membrane associated Fab fragment of immunoglobulin

what 2 polypeptide chains make up a t-cell receptor

• alpha a

• beta ß

THESE FORM ONE ANTIGEN BINDING SITE

each TCR chain has what 3 regions?

• variable domain (V)

• constant domain (C)

• transmembrane or membrane anchoring region

variable (V) domains of a and ß chains each have…

3 hypervariable regions (loops)

• CDR

CDR

complementarity-determining regions

structure of TCR resembles

single antigen-binding arm of B cell receptor (immunoglobulin)

• Fab fragment (membrane bound)

alpha chain locus

• located on chromosome 14

• variable domain similar to Ig light chan locus

  • composed of V AND J segments

  • V segment joined to J segment by somatic recombination

  • P and N nucleotides inserted at VJ junction

beta chain locus

• located on chromosome 7

• variable domain similar to Ig heavy chain locus

  • composed of V, J, and D segments

    • D segment joined to J segment

  • DJ segment joined to V segment

  • P and N nucleotides inserted at D, J, and V junctions

t-cell receptor diversity is generated by

gene rearrangement

gene rearrangement takes place during…

T cell development in thymus

RSS

recombination signal sequences

rare genetic defect due to absence of RAG proteins result in

SCID (severe combined immunodeficiency disease)

missense mutations resulting in RAG proteins with PARTIAL activity causes…

omenn syndrome

t cell receptors do not undergo any further diversification after

antigen stimulation

newly synthesized a and ß chains enter ER and associate with 4 invarient membrane proteins…

• delta

• epsilon

• gamma

• zeta

delta, epsilon, and gamma

• form dimers, called CD3

• genes located on chromosome 11

zeta

located pm chromosome 1

invarient membrane proteins

• transport to cell surface

• signal transduction

t-cell receptor complex:

• t-cell receptor

• CD3 proteins

• ζ protein (zeta)

individuals who lack CD3δ or CD3ε chains have

low TCR receptors due to inefficient transport of receptors to cell surface

second class of TCR

y and δ chains

• t cells referred to as y:d T cells

y and δ chains comprise approximately

1-5% of circulating t-cells

• function unknown

• not restricted to MHC presentation of peptide antigens

are a:ß and y:d receptors expressed together?

no, never

t-cells cannot recognize antigens directly, so they recognize…

peptide antigens bound to MHC molecules

antigen processing

breakdown of pathogen-derived protein antigens into peptides

antigen presentation

processed peptide carried by MHC molecule and displayed on the surface of an antigen presenting cell (APC)

classes of MHC molecules

• MHC class I

• MHC class II

MHC class I

present antigens from intracellular pathogens to CD8 t-cells

MHC class II

present antigens from extracellular pathogens to CD4 t-cells

CD8 t-cell (cytotoxic t cell)

• recognize intracellular antigens

• primary function is to kill cells infected with virus or other intracellular pathogen

• member of Ig superfamily proteins

CD4 t-cell (helper t cell)

• recognize extracellular antigens

• primary function to help other immune system t respond to extracellular pathogens

• member of Ig superfamily proteins

CD4 structure

four immunoglobulin domains (D1-D4) and a membrane spanning region

CD8 structure

• heterodimer of a and ß chain that have extended membrane-spanning region

CD8 binds to

the a3 domain of MHC class I

CD4 bind =s to

the ß2 domain of MHC class II

t cell antigen recognition:

by t cell receptor + CD8/CD4 molecules; CD8 and CD4 are considered t-cell co-receptors

MHC

major histocompatibility complex

• MHC molecules are glycoproteins

MHC class I molecule

• single membrane bound a (alpha) chain non-covalently linked to ß2-microglobulin

• alpha chain has three domains

  • a1, a2, a3

MHC class II molecule

• heterodimer of two membrane bound chains (a and ß)

• each chain has two domains

how long is MHC class I?

8-10 amino acids long

how long is MHC class II?

13-25 amino acids long

intracellular pathogens

• degradation of pathogen and antigens in cytosol of the infected cells

• pathogen-derived peptides enter ER and are loaded to MHC class I molecules

extracellular pathogens

• microorganisms and toxins taken up by phagocytosis and endocytosis

• degradation of proteins and loading onto MHC class II molecules in phagolysosomes and endocytotic vesicles

processing of antigens from intracellular pathogens

• proteins are degraded in the cytoplasm of the infected cells by a structure called proteasome

• proteasome are barrel shaped protein complex with proteolytic activities

• degraded proteins in the form of small peptides transported into ER lumen by TAP

TAP

transporter associated with antigen processing

peptides produced in the cytosol are transported into the

endoplasmic reticulum

what is the class I heavy chain stabilized by?

calnexin

• until ß2 microglobulin binds

the heterodimer of class I heavy chain and ß2m form the…

peptide loading complex

• also with calreticulin, tapasin, TAP, and ERp57

what forms the mature MHC class I molecule?

a peptide delivered by TAP that binds to the class I heavy chain

ERAP

endoplasmic reticulum aminopeptidase

• this shortens the peptide to fit the peptide-binding groove

bare lymphocyte syndrome or MHC class I immunodeficiency disease

• defective intracellular antigen processing due to nonfunctional TAP

• decreased levels of the cell surface MHC class I molecules

• chronic respiratory infections

processing of antigens from extracellular pathogens

• engulfment of extracellular pathogens and toxins

• formation of phagosome or endosome

• fusion of phagosome/endosome with lysosomes

• proteolytic degradation within phagolysosome

• binding of peptides with MHC class II molecules

• peptide loaded MHC class II molecules transported to cell surface

invarient chain prevents MHC class II molecules from

binding peptides in the endoplasmic reticulum

distribution of MHC class I molecules

• almost all cells of the body (not erythrocytes)

• this enables comprehensive surveillance by CD8 t-cells

distribution of MHC class II molecules

• constitutively expressed by antigen presenting cells

  • macrophages

  • B lymphocytes

  • dendritic cells (immature)

HLA

human leukocyte antigen complex

MHC is responsible for

rejection of tissue or organ transplant

MHC molecules encoded by a number of closely linked genes on

chromosome 6

• conventional gene configuration, no gene arrangement

numerous genetic variants in human population responsible for

host vs. graft OR graft vs. host

polygene (polygenic)

• multiple genes encode alpha chain of MHC I molecules

• multiple genes encode a and ß chains of MHC II molecules

• isotypes: proteins encoded by different genes

polymorphism (polymorphic)

• multiple alternative forms (alleles) of MHC I and MHC II genes in human population

• allotypes: proteins encoded by alleles of the gene

monomorphic

MHC class I and II genes with no polymorphism or alleles

oligomorphic

MHC class I and II genes with few alleles

homozygous

inheritance of same allele of the gene from both parents

heterozygous

inheritance of different allele of the gene from both parents

MHC polymorphism affects

the binding of peptide antigens and their presentation to t-cells

HLA typing

• HLA class I and HLA class II allotype combinations

• selection of donors and recipients for transplantation

• major mismatch during transplant of organs associated with graft rejection by recipient

• minor HLA mismatches overcome using immunosuppressive drugs

• during transplantation of bone marrow, allo-antigens associated with graft against recipients tissues