Chapter 32: ψ-Recognition in Antigen Presentation

"In the molecular theater of antigen presentation, ψ stages its most intimate performance — cells becoming storytellers, displaying fragments of their inner world for immune inspection."

32.1 The Molecular Stage of Self and Other

Antigen presentation represents one of biology's most sophisticated information transfer systems. Through this process, cells become molecular storytellers, displaying peptide fragments that reveal their internal state to surveying T cells. This final chapter of our endocrine orchestration explores how antigen presentation creates a continuous dialogue between cells and the immune system, enabling the recognition of both self and non-self at the molecular level.

Definition 32.1 (Antigen Presentation ψ-Complex): The presented peptide-MHC complex creates a recognition surface:

$\Psi_{presented} = \text{MHC} \otimes \text{peptide} \otimes \text{context}$

where:

• MHC provides the structural framework
• Peptide carries the information
• Context includes co-stimulatory molecules

This ternary complex enables T cells to "see" inside other cells.

32.2 The Architecture of MHC Molecules

MHC molecules are evolution's solution to displaying linear peptides for 3D recognition:

Theorem 32.1 (MHC-Peptide Binding): The binding affinity follows:

$K_d = K_0 \exp\left(-\frac{\Delta G_{binding}}{RT}\right)$

where $\Delta G_{binding}$ depends on:

• Anchor residue compatibility
• Peptide length (8-10 for MHC-I, 13-25 for MHC-II)
• Auxiliary contacts

Proof: Crystal structures reveal that MHC molecules form a groove with pockets that accommodate specific amino acid side chains. The binding energy comes from hydrogen bonds, van der Waals forces, and hydrophobic interactions. Each MHC allele has distinct pocket specificities, creating unique peptide-binding motifs. ∎

32.3 The Proteasome-TAP-MHC Pathway

MHC class I presentation involves an elaborate cellular machinery:

Definition 32.2 (Class I Processing Pathway):

$\text{Protein} \xrightarrow{\text{Proteasome}} \text{Peptides} \xrightarrow{\text{TAP}} \text{ER} \xrightarrow{\text{Loading}} \text{MHC-I-peptide}$

Key steps:

1. Proteasomal degradation: Proteins → 8-10mer peptides
2. TAP transport: Cytosol → ER lumen
3. Peptide loading complex: Quality control
4. Surface transport: ER → Golgi → membrane

This pathway continuously samples the cellular proteome.

32.4 Endocytic Pathways and MHC Class II

MHC class II molecules present extracellular antigens:

Theorem 32.2 (Class II Loading Dynamics): The peptide exchange reaction follows:

$\text{MHC-II-CLIP} + \text{peptide} \xrightleftharpoons[\text{HLA-DM}]{} \text{MHC-II-peptide} + \text{CLIP}$

where HLA-DM catalyzes peptide exchange.

The pathway involves:

• Endocytosis: Antigen uptake
• Lysosomal degradation: Proteins → peptides
• MIIC compartment: MHC-II loading
• Surface display: Stable complexes only

32.5 Cross-Presentation: Breaking the Rules

Dendritic cells can present extracellular antigens on MHC-I:

Definition 32.3 (Cross-Presentation Mechanisms):

$\text{Extracellular Ag} \xrightarrow{\text{DC}} \text{MHC-I presentation}$

Pathways include:

• Cytosolic: Endosome → cytosol → proteasome
• Vacuolar: Processing within endosomes
• Gap junction transfer: Direct peptide transfer

This enables priming of CD8+ T cells against tumors and pathogens that don't infect APCs.

32.6 The Immunological Synapse

T cell recognition creates a specialized interface:

Theorem 32.3 (Synapse Organization): The immune synapse shows concentric organization:

$\text{Synapse} = \text{cSMAC}_{(TCR-MHC)} + \text{pSMAC}_{(adhesion)} + \text{dSMAC}_{(signaling)}$

Creating:

• Central region: TCR-peptide-MHC clusters
• Peripheral ring: Adhesion molecules
• Distal zone: Large molecules excluded

This organization optimizes signaling and prevents non-specific activation.

32.7 Kinetic Proofreading and Specificity

T cells achieve remarkable specificity through kinetic proofreading:

Definition 32.4 (Serial Triggering Model):

$P_{activation} = \left(\frac{k_{on}}{k_{on} + k_{off}}\right)^n$

where $n$ represents the number of required signaling steps.

This creates:

• High specificity (self vs. non-self discrimination)
• Sensitivity (few peptide-MHC complexes needed)
• Serial engagement (one peptide-MHC triggers multiple TCRs)

32.8 Professional Antigen Presenting Cells

Different APCs serve distinct functions:

Dendritic Cells: Master presenters

• High MHC expression
• Constitutive processing
• Migration to lymph nodes
• T cell priming specialists

Macrophages: Inflammatory presenters

• Inducible MHC-II
• Phagocytic capacity
• Local presentation
• Effector phase

B Cells: Antigen-specific presenters

• BCR-mediated uptake
• Focused presentation
• T cell help recruitment

32.9 Self-Peptide Presentation

Most presented peptides are self-derived:

Theorem 32.4 (Self-Peptide Abundance):

$\frac{[\text{self-peptides}]}{[\text{foreign-peptides}]} > 10^4 \text{ (steady state)}$

Functions of self-presentation:

• Positive selection: Teaching T cells MHC restriction
• Peripheral survival: Tonic TCR signaling
• Negative selection: Deleting autoreactive cells
• Regulatory T cells: Maintaining tolerance

32.10 Altered Peptide Ligands and Molecular Mimicry

Modified peptides can alter T cell responses:

Definition 32.5 (APL Effects):

\text{Full agonist} \\ \text{Partial agonist} \\ \text{Antagonist} \\ \text{Altered specificity} \end{cases}$$ This explains: - **Viral escape**: Mutations avoiding recognition - **Molecular mimicry**: Self-cross-reactive responses - **Heteroclitic peptides**: Enhanced immunogenicity - **Altered peptide ligand therapy**: Modulating responses ## 32.11 Cancer and Altered Presentation Tumors evade immunity through presentation defects: **Loss of MHC-I**: Avoiding CD8+ T cells $$\downarrow \beta_2\text{-microglobulin} \rightarrow \text{No surface MHC-I}$$ **Immunoproteasome changes**: Altered peptide repertoire $$\text{Constitutive} \rightarrow \text{Immuno-proteasome} \rightarrow \text{Different peptides}$$ **Neo-antigen presentation**: Tumor-specific mutations $$\text{Mutation} \rightarrow \text{Novel peptide} \rightarrow \text{T cell recognition}$$ ## 32.12 Future Directions in Antigen Presentation Understanding presentation mechanisms enables new therapies: **Peptide Vaccines**: Designing optimal epitopes $$\text{Predict} \rightarrow \text{Synthesize} \rightarrow \text{Present} \rightarrow \text{Immunity}$$ **Artificial APCs**: Engineered presentation $$\text{Beads/cells} + \text{MHC-peptide} + \text{Costimulation}$$ **Presentation Enhancement**: Improving weak responses $$\uparrow \text{Processing} + \uparrow \text{Loading} = \uparrow \text{Presentation}$$ **Tolerogenic Presentation**: Inducing specific tolerance $$\text{Peptide} + \text{Regulatory context} \rightarrow \text{Tolerance}$$ **Exercise 32.1**: Calculate how many different peptides can be presented by a single MHC allele. Consider the binding motif constraints and the size of the human proteome. How does this change with infection? **Meditation 32.1**: Imagine the surface of every nucleated cell in your body continuously displaying fragments of internal proteins — a molecular confession of cellular state. This vast presentation creates your immunological self, the biochemical story of who you are at the molecular level. Antigen presentation reveals ψ's ultimate recognition system — the ability to fragment the world into peptides and reconstruct meaning through molecular display, creating an immune consciousness that surveils the boundary between self and other. *The Thirty-Second Echo*: In antigen presentation, ψ achieves its most intimate knowledge — learning to see inside itself through molecular mirrors, discovering that recognition of other requires first a deep understanding of self. [Continue to Part III: Immune Intelligence](../part-03-immune-intelligence/index.md) *Remember: Every cell in your body is constantly presenting its inner state to passing T cells — a continuous molecular dialogue that maintains your identity while protecting against invasion.*