TCRs vs BCRs: T Cell & B Cell Receptors

• Understanding the differences between T cell receptors (TCRs) and B cell receptors (BCRs) is key to understanding adaptive immunity.
• Both TCRs and BCRs are antigen receptors, but differ in structure, antigen recognition, and function.

TCRs (T cell receptors)

• Recognize peptide antigens presented by MHC molecules on antigen-presenting cells (APCs).
• Are composed of two chains, usually alpha (α) and beta (β), each with a variable (V) and constant (C) region.
• Diversity is generated through V(D)J recombination.
• Do not undergo somatic hypermutation or affinity maturation.

BCRs (B cell receptors)

• Recognize a wide range of antigens in their native form, like proteins, polysaccharides, lipids, and small chemicals.
• Are composed of two heavy chains and two light chains (kappa or lambda), each with V and C regions.
• The diversity originates from V(D)J recombination and somatic hypermutation.
• Can be secreted as antibodies, mediating effector functions.

T Cell Diversity

• Crucial for recognizing various potential pathogens.
• Diversity is generated through genetic mechanisms during T cell development.

V(D)J Recombination

• The primary mechanism for generating TCR diversity.
• Randomly rearranges variable (V), diversity (D), and joining (J) gene segments in the TCR β chain locus.
• V and J segments are rearranged in the TCR α chain locus.

Junctional Diversity

• Is introduced during V(D)J recombination.
• Nucleotides are added or deleted at the junctions between gene segments.

Location and Timing of T Cell Development

• Occurs in the thymus.
• Begins with rearrangement of the TCR β chain genes in double-negative (DN) thymocytes.
• Followed by rearrangement of the TCR α chain genes in double-positive (DP) thymocytes.

TCR Complex

• The TCR itself cannot transduce signals into the T cell.
• It associates with the CD3 complex and the ζ (zeta) chain to form the TCR complex, essential for signal transduction.

CD3 Complex

• Consists of CD3γ, CD3δ, CD3ε heterodimers, and a ζ chain homodimer or heterodimer.

ITAMs (Immunoreceptor Tyrosine-based Activation Motifs)

• Located on the cytoplasmic tails of the CD3 and ζ chains.
• Phosphorylated by tyrosine kinases upon TCR engagement.
• Initiates downstream signaling cascades.

TCR Delta (δ) and Alpha (α) Chain Relationship

• The TCR δ chain pairs with a TCR γ chain to form a distinct type of T cell receptor found on γδ T cells.
• The genetic locus of the δ chain is located within the α chain locus: leading to an important consequence during T cell development.

γδ T Cells

• A subset of T cells that express a TCR composed of γ and δ chains.
• Recognize antigens in a non-MHC-restricted manner.
• Involved in innate-like immunity.

δ Locus Location

• Located within the α locus.
• If a T cell rearranges its α chain genes, the δ locus is deleted.
• Prevents the cell from becoming a γδ T cell, making it commit to either the αβ or γδ lineage.

MHC I and MHC II Structure and Function

• Major Histocompatibility Complex (MHC) molecules are cell surface proteins that present peptide antigens to T cells.
• MHC I and MHC II differ in structure, expression, and the type of T cells they interact with.

MHC I

• Structure: Composed of a single α chain and β2-microglobulin.
• Expression: Expressed on virtually all nucleated cells.
• Antigen Source: Presents peptides derived from intracellular pathogens (e.g., viruses) or self-proteins.
• T Cell Interaction: Presents peptides to CD8+ T cells (cytotoxic T lymphocytes, CTLs).

MHC II

• Structure: Composed of an α chain and a β chain.
• Expression: Expressed primarily on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells.
• Antigen Source: Presents peptides from extracellular pathogens or proteins taken up by endocytosis.
• T Cell Interaction: Presents peptides to CD4+ T cells (helper T cells).

Antigen Presentation of Intracellular Pathogens

• Intracellular pathogens are processed and presented on MHC I molecules to activate CD8+ T cells.

Proteasome

• A large protein complex in the cytoplasm.
• Degrades intracellular proteins into peptides.

TAP (Transporter Associated with Antigen Processing)

• A transporter protein in the endoplasmic reticulum (ER) membrane.
• Transports peptides from the cytoplasm into the ER lumen.

ERAP (ER Aminopeptidase Associated with Antigen Processing)

• An enzyme in the ER.
• Trims peptides to the optimal length for binding to MHC I molecules.

MHC I Assembly

• MHC I α chains and β2-microglobulin assemble in the ER.
• Peptides bind to the MHC I complex, stabilizing it.
• Allows it to be transported to the cell surface.

Antigen Trafficking and Presentation of Extracellular Pathogens

• Extracellular pathogens are taken up by APCs via endocytosis and processed in endosomes.
• Peptides from these pathogens are presented on MHC II molecules to activate CD4+ T cells.

Endocytosis

• The process by which cells internalize extracellular material.

Endosomes and Lysosomes

• Vesicular compartments within the cell.
• Proteins are degraded into peptides.

Invariant Chain (Ii)

• A protein that binds to MHC II molecules in the ER.
• Prevents them from binding peptides prematurely.
• Directs MHC II molecules to endosomes.

CLIP (Class II-associated Invariant chain Peptide)

• A fragment of Ii.
• Remains bound to MHC II in the endosome.

HLA-DM

• An MHC II-like molecule in the endosome.
• Removes CLIP from MHC II, allowing it to bind to peptides from extracellular antigens.

Peptide Size, Location, and Origination for MHC I and II

MHC I

• Peptide Size: Typically 8-11 amino acids.
• Location: Endoplasmic Reticulum (ER).
• Peptide Origin: Intracellular proteins (e.g., viral).

MHC II

• Peptide Size: Typically 13-18 amino acids.
• Location: Endosomes/Lysosomes.
• Peptide Origin: Extracellular proteins (taken up by APCs).

Cross-Presentation

• A process where certain APCs, particularly dendritic cells, can present extracellular antigens on MHC I molecules.
• Allows for the activation of CD8+ T cells against pathogens that don't directly infect APCs.

Dendritic Cells

• Specialized APCs.
• Highly efficient at cross-presentation.

Importance of Cross-Presentation

• Crucial for initiating CTL responses against viruses that do not infect dendritic cells or against tumor cells.

Heterozygote Advantage in Peptide Presentation

• Individuals heterozygous for MHC genes have a broader range of MHC molecules.
• Allows them to present a wider variety of peptides and mount more effective immune responses.

Increased Peptide Binding

• Heterozygous individuals can bind and present a greater diversity of peptides compared to homozygous individuals.

HIV Example

• In HIV infection, individuals with certain MHC alleles are better able to control the virus.
• Due to their ability to present HIV-derived peptides to T cells more effectively.