Lecture 15: Antigen Processing and Presentation

Comprehensive vocabulary flashcards covering the cellular and molecular mechanisms of antigen processing and presentation by MHC Class I and Class II molecules.

Antigen Presentation

The immunological process acting as the interface between the innate and adaptive immune systems, wherein cells display peptide fragments on MHC molecules to allow T cells to detect intracellular and extracellular antigens.

T-Cell Receptor (TCR)

An antigen-specific surface receptor on T cells composed of an $\alpha$ chain and a $\beta$ chain, each containing a variable region and a constant region.

TCR Variable Regions

The antigen-specific binding sites on the TCR formed by $\text{V}_\alpha \text{J}_\alpha$ gene segments on the $\alpha$ chain and $\text{V}_\beta \text{D}_\beta \text{J}_\beta$ gene segments on the $\beta$ chain.

TCR Constant Regions

The structural, invariant regions of the TCR $\alpha$ and $\beta$ chains that anchor the receptor into the T-cell plasma membrane.

Clonal TCR Specificity

The principle that all individual T-cell receptors displayed across the surface of a single given T cell share identical variable regions and antigen specificity, having nothing different between them.

Major Histocompatibility Complex (MHC)

The most important tissue-matching group of genes, encoding specialized cell-surface glycoproteins that bind and present peptide antigens to T cells.

Human Leukocyte Antigen (HLA)

The designation used for the Major Histocompatibility Complex (MHC) gene cluster and its expressed protein molecules in humans.

MHC Class I (MHC-I)

A cell-surface molecule expressed on all nucleated cells that presents endogenous (intracellular) peptide antigens to CD8 T cells.

MHC Class II (MHC-II)

A cell-surface molecule expressed primarily on professional antigen-presenting cells that presents exogenous (extracellular) peptide antigens to CD4 T cells.

Professional Antigen-Presenting Cells (APCs)

Specialized immune cells—specifically dendritic cells, macrophages, and B cells—that express both MHC-I and MHC-II and function to activate naïve T cells.

Red Blood Cells (Erythrocytes)

Non-nucleated human cells that uniquely lack expression of MHC class I molecules.

Naïve T Cell

A mature T cell that has successfully left the thymus but has not yet encountered its specific cognate antigen presented on an MHC molecule.

Effector CD8 T Cell

An activated cytotoxic CD8 T cell that surveys MHC-I complexes and induces targeted killing of virally infected cells or cancer cells.

Self-Peptides

Normal host-derived peptides that constitute approximately $99\%$ of all peptides presented on MHC-I molecules, allowing T cells to establish and monitor what is normal 'self'.

Endogenous Antigens

Antigenic proteins originating inside the cell—such as normal self-proteins, viral proteins during infection, or mutated tumor antigens (~$1\%$ during disease)—that are degraded and displayed on MHC-I.

Exogenous Antigens

Antigens originating outside the cell that are internalized into intracellular vesicles via endocytosis or phagocytosis and processed for presentation on MHC-II.

High Endothelial Venule (HEV)

Specialized vascular site in the lymph-node cortex where circulating naïve T cells exit the bloodstream to enter lymphoid tissue and monitor antigen-bearing dendritic cells.

Draining Lymph Node

The secondary lymphoid organ where antigen-bearing dendritic cells arrive via lymphatic vessels and settle in T-cell areas to activate naïve T cells.

Classical MHC Class I Genes

Highly polymorphic human genes encoding classical MHC-I heavy chains, specifically HLA-A ($2980$ allotypes), HLA-B ($3700$ allotypes), and HLA-C ($2661$ allotypes).

Classical MHC Class II Genes

Highly polymorphic human genes encoding classical MHC-II $\alpha$ and $\beta$ chains, specifically HLA-DP, HLA-DQ, and HLA-DR.

Non-Classical MHC Genes

MHC genes (such as HLA-E, HLA-F, HLA-G in class I, and HLA-DM, HLA-DO in class II) that present non-classical antigens like carbohydrates and lipids or regulate peptide loading.

MHC Class I Heavy Chain

A polymorphic transmembrane polypeptide chain folded into three extracellular domains ($\alpha_1$, $\alpha_2$, and $\alpha_3$) that pairs with $\beta_2$-microglobulin.

\beta_2-microglobulin (\beta_2m)

An invariant, non-transmembrane protein located in the ER lumen that non-covalently associates with the MHC class I heavy chain to stabilize the complex.

MHC Class II Heterodimer

A surface complex composed of two transmembrane chains ($\alpha$ and $\beta$), each contributing two domains ($\alpha_1, \alpha_2$ and $\beta_1, \beta_2$).

MHC Class I Peptide-Binding Cleft

A closed-ended binding groove formed by the $\alpha_1$ and $\alpha_2$ domains that accommodates peptides consisting of $8\text{--}11$ amino acids (most often $9$).

MHC Class II Peptide-Binding Cleft

An open-ended binding groove formed by the $\alpha_1$ and $\beta_1$ domains that accommodates extended peptides consisting of $11\text{--}30$ amino acids.

MHC Polymorphism

The extensive sequence variation among classical MHC alleles that alters amino acid residues in the binding cleft, changing its shape and determining which peptides can bind.

Proteasome

A cylindrical cytosolic protein degradation complex that cleaves intracellular self and pathogen proteins into peptide fragments for MHC-I presentation.

TAP (Transporter Associated with Antigen Processing)

An ATP-dependent transporter in the endoplasmic reticulum membrane that shuttles peptide fragments from the cytosol into the ER lumen.

Endoplasmic Reticulum Aminopeptidase (ERAP)

An ER aminopeptidase that removes amino acid residues sequentially from the amino (N) terminus of peptides that are too long, trimming them into nonamers to fit the MHC class I cleft.

Calnexin

A membrane-bound ER chaperone protein that stabilizes the newly synthesized MHC class I heavy chain until $\beta_2$-microglobulin binds.

Peptide-Loading Complex (PLC)

A multiprotein assembly in the ER formed by TAP, tapasin, ERp57, calreticulin, the MHC class I heavy chain, and $\beta_2\text{m}$ that loads peptides onto MHC-I.

Tapasin

A chaperone protein within the peptide-loading complex that bridges the MHC class I heavy chain to TAP for efficient peptide acquisition.

Endosomal Acidification

The decrease in pH occurring within maturing intracellular vesicles that activates previously inactive endosomal proteases to degrade extracellular antigens into peptide fragments.

Endocytic PRR (Pattern Recognition Receptor)

A cell-surface pattern recognition receptor on an APC that binds an antigen to trigger endocytosis or phagocytosis for processing along the MHC-II pathway.

Invariant Chain (Ii)

A specialized protein that binds the MHC class II peptide-binding cleft in the ER, preventing premature binding of endogenous peptides or misfolded proteins.

CLIP (Class II-Associated Invariant Chain Peptide)

The small peptide fragment of the invariant chain that remains bound in the MHC class II cleft after proteolytic cleavage of the invariant chain inside vesicles.

HLA-DM (DM / H2-M)

A non-classical MHC class II molecule (called H2-M in mice) that catalyzes the release of CLIP from the MHC-II cleft, allowing high-affinity antigenic peptides to bind.

Cross-Presentation

A specialized pathway in dendritic cells where internalized exogenous viral or tumor antigens are diverted into the cytosol, degraded by the proteasome, and loaded onto MHC-I to activate CD8 T cells without direct infection of the APC.

Bacterial Superantigen

A bacterial toxin (e.g., staphylococcal enterotoxin [SE] or toxic shock syndrome toxin-1 [TSST-1]) that binds both MHC class II and TCR with high affinity outside the peptide cleft, bridging them non-specifically to hyperactivate $> 20\%$ of T cells.