Chapter 5: Antigen Recognition by T Lymphocytes
Contents
T-cell receptor diversity
5-1 The T-cell receptor resembles a membrane-associated Fab fragment of immunoglobulin
5-2 T-cell receptor diversity is generated by gene rearrangement
5-3 Expression of the T-cell receptor on the T-cell surface requires association with additional proteins
5-4 A distinctive population of T cells expresses a second class of T-cell receptor with γ and δ chains
Antigen processing and presentation
5-5 T-cell receptors recognize peptide antigens bound to MHC molecules
5-6 Two classes of MHC molecule present peptide antigens to two types of T cell
5-7 MHC class I and class II molecules have similar structures
5-8 MHC class I binds shorter and more precisely defined peptides than MHC class II
5-9 MHC class I and class II bind peptides in different intracellular compartments
5-10 Peptides produced in the cytosol are transported to the endoplasmic reticulum for binding to MHC class I
5-11 MHC class I binds peptides in the context of a highly specific peptide-loading complex
5-12 All cells express MHC class I, whereas MHC class II is mainly expressed by professional antigen-presenting cells
5-13 Invariant chain prevents MHC class II from binding peptides in the endoplasmic reticulum
5-14 Cross-presentation enables extracellular antigens to be presented by MHC class I
The major histocompatibility complex
5-15 Human MHC diversity is the product of gene families and genetic polymorphisms
5-16 HLA class I and class II genes occupy separate regions of the HLA complex
5-17 Proteins involved in antigen processing and presentation are encoded by genes in the HLA class II region
5-18 Some MHC class I and class II genes are highly polymorphic
5-19 Selection by infectious disease is a likely major cause of HLA class I and class II diversity
5-20 Human populations all maintain a diversity of HLA class I and class II alleles
Key Terms and Processes Covered
Types of TCRs and associated proteins
Generation of TCR diversity
Process of antigen processing, presentation and recognition (TCR, MHC I and II)
MHC = Major Histocompatibility Complex (also called HLA in humans)
Transplantation
T-cell Receptor Diversity
5-1 The T-cell receptor resembles a membrane-associated Fab fragment of immunoglobulin
TCRs (T-cell Receptors) are similar to BCRs (B-cell Receptors):
They possess an antigen-binding site, a constant region and a variable region.
They have complementarity-determining regions (CDR regions).
They are membrane-bound and comprise two polypeptide chains: alpha and beta.
TCR undergoes a transition from germline to rearranged DNA during development.
All TCRs on a single T cell are identical, while different T cells express different TCRs.
5-2 T-cell receptor diversity is generated by gene rearrangement
TCR is produced similarly to BCR prior to encountering an antigen.
TCR consists of two polypeptide chains:
The alpha chain (analogous to the light chain of a BCR) is formed by V and J gene segment joining.
The beta chain (analogous to the heavy chain of a BCR) is formed by V, D, and J gene segment joining.
Rearrangement occurs in the thymus, producing a fully functional polypeptide with a leader peptide region and correctly assembled variable (V), constant (C), and membrane regions.
5-3 Expression of the T-cell receptor on the T-cell surface requires association with additional proteins
CD3 complex: Composed of ε, γ, δ, and ζ chains, fulfilling crucial roles such as:
Facilitating transport of TCR to the cell surface
Enabling signal transduction, allowing extracellular signals to be transmitted into the cell
5-4 A distinctive population of T cells expresses a second class of T-cell receptor with γ and δ chains
TCRα (TCR alpha) and TCRβ (TCR beta) represents 95% of T cells while TCRγ (TCR gamma) and TCRδ (TCR delta) account for 5%.
TCRγ and TCRδ are predominant in epithelial tissues and have the ability to recognize antigens beyond those presented by MHC molecules.
Antigen Processing and Presentation
5-5 T-cell receptors recognize peptide antigens bound to MHC molecules
Terms to Know:
Antigen Processing: The process in which antigens are broken down into peptide fragments that are displayed on the cell surface.
Antigen Presentation: The display of antigenic peptides on MHC molecules at the surface of antigen-presenting cells (APCs).
Professional APC: Dendritic cells, macrophages, and B cells that are particularly effective in presenting antigens.
5-6 Two classes of MHC molecule present peptide antigens to two types of T cell
MHC Class I and Class II have structural similarities but functionally differ in their source of peptides and interaction with T cells.
5-7 MHC class I and class II molecules have similar structures
Both MHC classes have similar overall structure, including a peptide-binding groove and a stable region composed of β2-microglobulin (specific to MHC class I).
5-8 MHC class I binds shorter and more precisely defined peptides than MHC class II
MHC Class I typically binds peptides that are 8-10 amino acids in length, whereas MHC Class II can present peptides of 13-25 amino acids long.
Each MHC molecule binds a single peptide at a time but can potentially accommodate numerous different peptide types over time.
5-9 MHC class I and class II bind peptides in different intracellular compartments
The vesicular system involves vesicles and organelles such as the Golgi apparatus and the endoplasmic reticulum, serving as distinct compartments for peptide loading of MHC Class I and II.
5-10 Peptides produced in the cytosol are transported to the endoplasmic reticulum for binding to MHC class I
Both self and foreign proteins are translated in the cytosol. Mismatched proteins are typically directed towards the proteasome for degradation.
During an infection, the cellular machinery modifies proteasomes to catalyze the production of peptides optimized for MHC Class I loading, transforming from standard proteasome to immunoproteasome.
5-11 MHC class I binds peptides in the context of a highly specific peptide-loading complex
Steps include IFN-gamma inducing changes to proteasomes, resulting in the formation of immunoproteasomes that produce MHC I-binding peptides, which are then transported to the ER by TAP (Transporter Associated with Antigen Processing). Chaperone proteins facilitate proper folding and loading of the peptide onto MHC I.
5-12 All cells express MHC class I, whereas MHC class II is mainly expressed by professional antigen-presenting cells
Presence of MHC class I across all cell types enables them to present endogenous antigens to CD8 T cells.
MHC class II is predominantly found on specialized APCs, increasing their antigen-presenting capabilities.
5-13 Invariant chain prevents MHC class II from binding peptides in the endoplasmic reticulum
The invariant chain blocks premature peptide binding to MHC class II within the ER, facilitating appropriate antigen presentation only after the MHC class II has reached endocytic vesicles.
5-14 Cross-presentation enables extracellular antigens to be presented by MHC class I
Cross-presentation allows professional APCs to present exogenous antigens to CD8 T cells by loading these antigens onto MHC class I molecules, crucial for initiating cytotoxic responses.
The Major Histocompatibility Complex
5-15 Human MHC diversity is the product of gene families and genetic polymorphisms
MHC diversity is characterized by the presence of multiple alleles resulting from gene family expansion and varying polymorphisms among populations.
5-16 HLA class I and class II genes occupy separate regions of the HLA complex
HLA genes are organized on a specific region of chromosome 6. Grouping allows for coordinated expression of MHC genes.
5-17 Proteins involved in antigen processing and presentation are encoded by genes in the HLA class II region
This region has additional genes that directly influence the antigen processing pathway, impacting the immune response triggered by antigen presentation.
5-18 Some MHC class I and class II genes are highly polymorphic
High polymorphism in MHC class I and II genes results in a broad range of peptide binding capabilities, enhancing immune defense
5-19 Selection by infectious disease is a likely major cause of HLA class I and class II diversity
Increased diversity likely offers a selective advantage for populations under various infectious pressures, resulting in a greater number of alleles maintained across populations.
5-20 Human populations all maintain a diversity of HLA class I and class II alleles
The maintenance of a diverse set of HLA alleles is crucial for effective immune responses against pathogens, supporting survival and health.