1. Antigen recognition by T
lymphocytes
Dr. Glorivee Rosario-Pérez
BIOL 4056
Parham P. (2009). The Immune System. Third Edition. Garland Publishing, New York.
3. T cell receptor vs Immunoglobulin
T cell receptor Immunoglobulin
Membrane-bound glycoprotein Membrane-bound glycoprotein
It is composed of two different chains and has one antigen-
It is composed of two different chains and has one antigen- binding site.
binding site.
Always membrane bound Membrane bound
No secreted form Secreted form
Variable region (binds antigen)
Variable region (binds antigen)
Constant region
Constant region
During B cell development, gene rearrangement produces
During T cell development, gene rearrangement produces sequence variability in the variable regions of the
sequence variability in the variable regions of the T cell immunoglobulin.
receptor.
After the B cell is stimulated with antigen, occur mutation in
After the T cell is stimulated with antigen, there is no further the antigen-binding site and switching of constant region
mutation in the antigen-binding site and there is no switching isotype.
of constant region isotype.
T cell receptors are used only as receptors to recognize Immunoglobulin serve as both recognition and effector
antigen molecules
15. CD8
Are cytotoxic.
Their main function is to kill cells that have
become infected with a virus or some other
intracellular pathogen.
This response prevents the multiplication of
the pathogen and further infection of healthy
cells.
16. Help other cells of the immune system to
respond to extracellular sources of infection.
Two subclasses:
TH1 – activate tissue macrophages to
phagocytose and kill extracellular pathogens,
and to secrete cytokines and other active
molecules that affect the course of the immune
response.
TH2 – involved mainly in stimulating B cells to
make antibodies, which bind to extracellular
bacteria and virus particles.
A T cell receptor consist of two different polypeptide chains, called the T cell receptor α chain (TCR α ) and the T cell receptor β chain (TCR β ). Comparison of the amino acid sequences of the T cell receptor alpha and beta chains from different T cell clones shows that they are organized into variable regions (V regions) and constant region (C regions), like those found in immunoglobulin chains. Each chain consists of an amino terminal V domain, followed by a C domain, and then a membrane-anchoring domain. Immunoglobulins possess two or more binding sites for antigen; this supports the interactions of soluble antibody with the repetitive antigens found on the surfaces of microorganisms. T cell receptors possess a single binding site for antigen and are used only as cell surface receptors for antigen, never as soluble antigen binding molecules. Antigen binding to T cell receptors occurs always in the context of two opposing cell, thus achieving multipoint attachment.
The human T cell alpha chain is on chromosome 14 and the beta chain in on chromosome 7. The organization of the gene segments encoding T cell receptor alpha and beta chains is essentially like that of the immunoglobulin gene segments. The main difference is the simplicity of the T cell receptor C region: there is only one C α gene, and, although there are two C β genes, no functional distinction between them is known. The T cell receptor alpha chain locus contain sets of V and J gene segments (similar to an immunoglobulin light chain locus). The beta chain locus contain D gene segments in addition to V and J gene segments (similar to an immunoglobulin heavy chain locus).
T cell receptor gene rearrangement occurs during T cell development in the thymus. In the alpha chain gene, a V gene segment is joined to a J gene segment by somatic DNA recombination to make the V region sequence; in the beta chain gene, recombination first joins a D and a J gene segment, which are then joined to a V gene segment. After gene rearrangement functional alpha and beta chain genes consist of exons encoding the leader peptide, V region and C region, as well as the membrane spanning region. Upon transcription , the primary RNA transcript is spliced to remove the introns and is processed to give mRNA. Translation of the alpha and beta chain mRNA produces alpha and beta chains, respectively. Like all proteins destined for the cell membrane, newly synthesized alpha and beta chians enter the endoplasmic reticulum. There they pair to form the alpha:beta T cell receptor.
The functional antigen receptor on the surface of T cell is composed of eight polypeptides and is called the T cell receptor complex. The α and β chains bind antigen and form the core T cell receptor (TCR). They associate with one copy each of CD3 γ and CD3 δ and two copies each of CD3 ε and the ζ chain. These associated invariant polypeptides are necessary for transport of newly synthesized TCR to the cell surface and for transduction of signals to the cell’s interior after the TCR has bound antigen.
The α : β T cell receptor an the γ : δ T cell receptor have similar structures, but they are encoded by different sets of rearranging gene segments and have different functions. T cells behavior γ : δ receptors comprise about 1-5% of the T cells found in the circulation, but they can be the dominant T cell population in epithelial tissue. The immune function of γ : δ cells is less well defined than that of α : β T cells, as are antigens to which these cells respond and the ligands that their receptors engage.
The antigens recognizes by T cells are peptides that arise from the breakdown of macromolecular structures, the unfolding of individual proteins, and their cleavage into short fragments. These events constitute antigen processing. For a T cell receptor to recognize a peptide antigen, the peptide must be bound by an MHC molecule and displayed at the cell surface, a process called antigen presentation.
Circulating α : β T cells fall into one two mutually exclusive classes: one is defined by expression of the CD4 glycoprotein on the cell surface and the other by expression of the CD8 glycoprotein.
The MHC molecules are crucial in safeguarding that the appropriate class of T cells is activated in response to a particular source of infection. MHCI present antigens of intracellular origin to CD8 T cells, whereas MHCII molecules present antigens of extracellular origin to CD4 T cells.
The CD8 co-receptor binds to the α 3 domain of the MHC class I heavy chain, ensuring that MHCI molecules present peptides only to CD8 T cells. In complementary fashion, the CD4 co-receptor binds to the β 2 domain of MHCII molecules, ensuring that peptides bound by MHCII stimulate only CD4 T cells.
The peptide antigens that are bound and presented by MHC molecules are generated inside cells of the body by the breakdown of large protein antigens. Proteins derived from intracellular and extracellular antigens are present in different intracellular compartments. They are processed into peptides by two intracellular pathways of degradation, and bind to the two classes of MHC molecule in separate intracellular compartments. Peptide derived from the degradation of intracellular pathogens are formed in the cytosol and delivered to the endoplasmic reticulum. This is where MCH I molecules bind peptides. In contrast, extracellular microorganisms and proteins are taken up by cells via phagocytosis and endocytosis and are degraded in the lysosomes and other vesicles of the endocytic pathways. It is in these cellular compartments that MHC II molecules bind peptides.
Formation and transport of peptides that bind to MHC class I molecules. In all cells, proteosomes degrade cellular proteins that are poorly folded, damaged, or unwanted. When a cell becomes infected, pathogen-derived proteins in the cytosol are also degraded by the proteosome. Peptides are transported from the cytosol into the lumen of the endoplasmic reticulum by the protein called transporter associated with antigen processing (TAP), which is in the endoplasmic reticulum membrane.
MHC class I heavy chains assemble in the endoplasmic reticulum with the membrane-bound protein calnexin. When this complex binds β 2 -microglobulin the partly folded MHC I molecule is free from calnexin and then associates with the TAP-1 subunit of TAP by interacting with the TAP-associated protein tapasin and the chaperone protein calreticulin. The MHC class I molecule is retained in the endoplasmic reticulum until it binds a peptide, which completes the folding of the molecule. The peptide:MHCI complex is then released from tapasin and calreticulin, leaves the endoplasmic reticulum, and is transported to the cell surface.
Peptides derived from extracellular antigens and pathogens. Extracellular material is taken up by endocytosis and phagocytosis (by neutrophils and macrophages) into the vesicular system of the cell, in this case a macrophage. Proteases in these vesicles break down proteins to produce peptides that are bound by MHCII, which have been transported to the vesicle via endoplasmic reticulum and the Golgi apparatus. The peptide:MHCII complex is transported to the cell surface in outgoing vesicles. These membrane-bound vesicles become part of an interconnected vesicle system that carries materials to and from the cell surface. As vesicles travel inwards from the plasma membrane, their interiors become acidified by the action of proton pumps in the vesicle membrane and they fuse with other vesicles, such as lysosomes, that contain proteases and hydrolases that are active in acid conditions. = phagolysosomes.
MHC II alpha and beta chain are assemble with an invariant chain in the endoplasmic reticulum; this complex is transported to the acidified vesicles of the endocytic system. The invariant chain is broken down, leaving just a small fragment called class II-associated invariant chain peptide (CLIP) attached in the peptide-binding site. The vesicle membrane protein HLA-DM catalyzes the release of the CLIP fragment and its replacement by a peptide derived from endocytosed antigen that has been degraded within the acidic interior of the vesicles.
All the cells of the body express MHCI constitutively, and as all cell types are susceptible to infection by viral pathogens, this enables comprehensive surveillance by CD8 T cells. The erythrocyte in one cell type that lacks MHCI. MHCII are, in contrast, constitutively expressed on only a few cell types, which are cells of the immune system specialized for the uptake processing, and presentation of antigens from the extracellular environment. This distribution is consistent with MHCII function, alerting CD4 T cells to the presence of extracellular infections.
