Immunology: Chapter 5

What is the primary function of the TCR?

Recognition of antigen presented on MHC molecules; not secreted; no effector functions like antibodies.

TCRs are composed of which chains?

An alpha chain and a beta chain (α and β); each has a variable and constant region.

What type of antigen do TCRs recognize?

Linear peptides presented on MHC molecules; TCRs cannot bind to intact antigens.

What type of antigens do BCRs bind?

BCRs bind a wide range of antigens in their native form, including proteins, carbohydrates, lipids, and even DNA.

What is the CD3 complex?

Invariant membrane proteins (γ, δ, ε) that, along with ζ chains, associate with TCR for signaling and surface expression.

What happens if CD3δ and CD3ε are knocked out?

TCR signaling is reduced, and TCR expression on the cell surface is impaired, leading to immunodeficiency.

What is the role of the ζ chain in TCR signaling?

It transduces signals into the T cell's interior upon antigen recognition; part of the TCR complex.

What is the genetic organization of the α-chain locus?

Located on chromosome 14; contains V and J segments; ~80 V segments and ~61 J segments.

What is the genetic organization of the β-chain locus?

Located on chromosome 7; contains V, D, and J segments; multiple attempts at rearrangement possible due to Dβ1/Jβ1 and Dβ2/Jβ2 clusters.

What is the difference between TCR α and β chain recombination attempts?

The β chain can have up to 4 attempts (2 per chromosome), while the α chain has multiple V and J segments and homologous chromosomes for retries.

What enzyme complex is involved in TCR gene rearrangement?

RAG1 and RAG2 (Recombination Activating Genes) along with other DNA-modifying enzymes.

What are RSS sequences?

Recombination Signal Sequences; serve as landing pads for RAG1 and RAG2 during somatic recombination.

What is junctional diversity, and how does it affect the TCR?

Random addition of nucleotides at V(D)J junctions, creating CDR3 regions with immense diversity.

What is the structure of the TCR complex on the surface of a T cell?

8 polypeptides: α and β chains (antigen recognition), 2 ζ chains (signaling), and the CD3 complex (γ, δ, ε for signaling and transport).

How does TCR diversity compare to BCR diversity?

TCR diversity: ~5 x 10^13; BCR diversity: ~10^18.

What is the significance of the Delta locus in the TCR genes?

The entire Delta locus is embedded within the Alpha locus on chromosome 14; rearrangement of the Alpha locus deletes the Delta locus.

What is the significance of 2 D segments in Delta chain rearrangement?

Two D segments can be incorporated, increasing junctional diversity in the Delta chain's CDR3 region.

What is the percentage of γδ T cells in the total T cell population?

1-5% of total T cells; can be dominant in epithelial tissues.

What type of antigen recognition is unique to γδ T cells?

They are not restricted by MHC presentation and do not require co-receptors like CD4 or CD8.

What is polymorphism in MHC molecules?

Genetic variation across the population; thousands of different alleles exist for MHC genes.

What is an allele in the context of MHC?

A variant form of a gene; different nucleotide sequences leading to differences in amino acid sequences and binding grooves.

How does MHC diversity differ from TCR diversity?

MHC diversity is across the population (polymorphism); individual has a limited number (usually 12 if heterozygous), while TCR diversity is within the individual (millions of specificities).

What is the term used to describe MHC binding to many different peptides?

Promiscuous or degenerate binding; one MHC molecule can bind ~10,000 different peptides over a lifetime.

What does MHC class I present, and to which T cells?

Presents peptides from intracellular pathogens to CD8+ cytotoxic T cells.

What does MHC class II present, and to which T cells?

Presents peptides from extracellular pathogens to CD4+ helper T cells.

What are CD4 and CD8 molecules?

Co-receptors that stabilize interactions between the TCR and MHC-peptide complex; CD4 binds MHC II, CD8 binds MHC I.

What are the effector functions of CD8+ T cells?

Kill infected cells by inducing apoptosis via cytotoxins.

What are the effector functions of CD4+ T cells (Th1 and Th2)?

Th1: activate macrophages via IFN-γ; Th2: activate B cells via IL-4 and IL-5, promote isotype switching to IgE.

Can TCRs be secreted like antibodies?

No; TCRs are always membrane-bound and function only in cell-cell interactions.

How are T cells classified based on TCR type?

αβ T cells (adaptive, most common); γδ T cells (innate-like, less common, ~1-5%).

What is required for antigen recognition by a TCR?

Peptide presented on an MHC molecule; TCR binds both the peptide and the MHC.

What is the key difference between Ig and TCR antigen recognition?

TCRs bind one type of antigen, a linear peptide, presented on MHC; Igs can bind many antigen types (proteins, carbohydrates, lipids) in their native form.

Why can’t TCRs bind soluble antigens like BCRs?

TCRs only recognize peptides bound to MHC on another cell’s surface; they function in cell-to-cell contact, not as secreted molecules.

What are the 2 classes of MHC molecules, and what do they present?

MHC I: intracellular antigens to CD8+ T cells; MHC II: extracellular antigens to CD4+ T cells.

What are the main differences in antigen processing for MHC I and II?

MHC I: peptides generated by proteasome (cytosolic pathway); MHC II: peptides from phagocytosed or endocytosed material (endosomal pathway).

How does MHC diversity arise?

Polymorphism in the population; no somatic recombination or mutation like TCRs/BCRs.

How many different MHC molecules does a heterozygous individual typically express?

12 total (6 class I: HLA-A, B, C from both parents; 6 class II: HLA-DP, DQ, DR from both parents).

What term describes MHC’s ability to bind many peptides?

Promiscuous or degenerate binding.

What is the relationship between MHC and TCR diversity?

MHC diversity is limited and inherited; TCR diversity is generated in each individual via somatic recombination.

How does the TCR recognize antigens?

It recognizes both the peptide and the MHC molecule simultaneously in the peptide:MHC complex.

What is the role of the α1 and α2 domains in MHC class I?

They form the peptide-binding groove; α3 and β2 microglobulin support structure.

What is the structure of MHC class II?

Two chains: α (α1, α2) and β (β1, β2); peptide-binding groove is formed by α1 and β1.

What are the functions of CD4 and CD8 co-receptors?

CD4 binds MHC II and helps activate helper T cells; CD8 binds MHC I and helps activate cytotoxic T cells.

How do CD4+ T cells differentiate into subsets?

TH1: activate macrophages (via IFN-γ); TH2: help B cells produce antibodies (via IL-4, IL-5); TH17: inflammatory; Treg: suppress immune responses; Tfh: help B cells in germinal centers.

What is the major cytokine produced by TH1 cells?

Interferon-gamma (IFN-γ).

What is the major cytokine produced by TH2 cells?

Interleukin-4 (IL-4).

What is the main effector function of CD8+ cytotoxic T cells?

Induce apoptosis in infected cells using cytotoxins like perforin and granzymes.

What is the percentage breakdown of αβ vs γδ T cells in the body?

αβ T cells: 95-99% of total T cells; γδ T cells: 1-5%, often in epithelial tissues.

Why are γδ T cells considered part of the innate immune system?

They recognize antigens without MHC presentation and act rapidly, similar to NK cells.

What is the main structural similarity between αβ TCRs and BCRs?

Both have variable (V) and constant (C) regions; both use somatic recombination.

What is the main structural difference between αβ TCRs and BCRs?

TCRs are always membrane-bound and recognize only peptides on MHC; BCRs can be secreted (antibodies) and bind various antigen types.

What is the relationship between TCR variable domains and CDRs?

CDR1 and CDR2 are encoded within the V segment; CDR3 arises from junctional diversity (VDJ or VJ joining).

Why do TCRs have no effector function like antibodies?

TCRs only serve as antigen recognition molecules; effector functions (e.g., killing, cytokine release) are carried out by the T cell itself.

What is the analogy between CD3 complex and BCR signaling?

CD3 (γ, δ, ε) and ζ chains in TCR complex = Igα and Igβ in BCR complex; both transmit signals after antigen recognition.

What happens when a productive TCR rearrangement occurs at the α-chain locus?

The Delta locus (embedded within the α-chain locus) is deleted and inactivated.

How does the Delta chain add diversity to the TCR?

Two D segments can be incorporated (V-D-D-J), increasing junctional diversity.

What type of antigens do BCRs bind compared to TCRs?

BCRs bind native antigens of various types (proteins, lipids, carbs, DNA); TCRs bind only peptides on MHC.

What is the only type of antigen that αβ TCRs can recognize?

Protein-derived linear peptides presented by MHC molecules.

What does it mean that TCRs and BCRs have clonal distribution of specificity?

Each T or B cell expresses a unique receptor that binds a specific antigen; diversity is generated by gene rearrangement.

How is diversity generated in TCRs and BCRs?

Somatic recombination of V(D)J gene segments, junctional diversity, and (for BCRs) somatic hypermutation and isotype switching.

Where does TCR rearrangement occur?

In the thymus during T-cell development.

What enzyme complex facilitates TCR gene rearrangement?

RAG1 and RAG2, along with other DNA-modifying enzymes.

What do recombination signal sequences (RSS) do in TCR rearrangement?

They serve as landing pads for RAG1 and RAG2 to guide recombination of V, D, and J segments.

What is the general recombination pattern for the β-chain of TCRs?

V-D-J recombination: V to DJ segments.

What is the general recombination pattern for the α-chain of TCRs?

V-J recombination only; no D segment in the α-chain.

What chromosome contains the α-chain and δ-chain loci for TCRs?

Chromosome 14.

What chromosome contains the β-chain and γ-chain loci for TCRs?

Chromosome 7.

What happens to the δ-chain when α-chain rearrangement occurs?

The δ-chain locus is located between the V and J of the α-chain; it is deleted and inactivated when α-chain rearrangement happens.

What is the purpose of the CD3 complex in the TCR structure?

CD3 complex (γ, δ, ε) plus ζ chains stabilize the TCR and transmit intracellular signals after antigen recognition.

Why is the TCR α:β heterodimer alone not functional?

It requires the CD3 complex and ζ chains for surface expression and signal transduction.

What happens to TCR expression and signaling if CD3δ and CD3ε are knocked out?

Surface expression of TCR is low; signaling is impaired, leading to immunodeficiency.

What is the TCR complex composed of?

8 polypeptides: α and β chains (antigen recognition), 2 ζ chains (signaling), and CD3 complex (γ, δ, ε for signaling).

What is the role of the ζ chains in the TCR complex?

Transmit activation signals into the T cell after antigen recognition by the TCR.

Can a T cell express both αβ and γδ TCRs?

No; a T cell expresses either αβ or γδ TCRs, never both.

What percent of T cells express γδ TCRs?

1-5% of total T cells; can be dominant in epithelial tissues.

What is the role of γδ TCRs in the immune response?

They recognize antigens without MHC restriction and act in an innate-like manner, often in barrier tissues.

What is unique about the δ-chain rearrangement?

It can include two D segments (V-D-D-J) to increase junctional diversity.

What is the functional consequence of the γδ TCR not requiring MHC presentation?

γδ T cells can recognize antigens directly without restriction to MHC, unlike αβ T cells.

What is the effect of multiple D segments in the δ-chain?

Increases junctional diversity and the variability of the CDR3 region.

What is the major difference in antigen recognition between BCRs and TCRs?

BCRs recognize a variety of native antigens (proteins, lipids, DNA), while TCRs only recognize peptide antigens presented on MHC.

How is diversity generated within the αβ TCR repertoire?

Somatic recombination of V(D)J segments, junctional diversity at recombination sites, and combinatorial pairing of α and β chains.

What is the significance of TCR’s single antigen specificity?

Each T cell clone expresses a unique TCR specific to one peptide:MHC complex; this ensures precise recognition.

What are the requirements for TCR activation?

Binding of the TCR to peptide:MHC complex plus co-receptor engagement (CD4 or CD8) and additional signaling molecules (e.g., CD28).

What is the primary role of CD4+ T cells in immunity?

Helper functions: activate macrophages, help B cells produce antibodies, secrete cytokines to modulate immune responses.

What is the primary role of CD8+ T cells in immunity?

Cytotoxic function: recognize infected cells via MHC I and induce apoptosis to prevent pathogen spread.

What are the effector cytokines of TH1 cells?

Interferon-gamma (IFN-γ) to activate macrophages and enhance phagocytosis.

What are the effector cytokines of TH2 cells?

Interleukin-4 (IL-4) and IL-5; IL-4 activates B cells and induces IgE production.

What are the effector cytokines of TH17 cells?

Interleukin-17 (IL-17); promotes inflammation and recruits neutrophils.

What are the effector cytokines of T follicular helper (Tfh) cells?

Interleukin-21 (IL-21); helps B cells in germinal centers for affinity maturation and isotype switching.

What are the effector cytokines of regulatory T cells (Treg)?

Interleukin-10 (IL-10) and TGF-β; suppress immune responses to maintain tolerance.

How do naive T cells get activated?

By interacting with antigen-presenting dendritic cells in secondary lymphoid tissues, receiving signals from TCR, co-receptors, and co-stimulatory molecules.

What are the 3 signals required for naive T cell activation?

Signal 1: TCR binding to peptide:MHC complex; Signal 2: Co-stimulation via CD28 on T cell binding to B7 on APC; Signal 3: Cytokines to direct differentiation.

What happens if a naive T cell encounters antigen without co-stimulation?

It becomes anergic (non-responsive) and cannot be activated.

What happens when a CD8 T cell recognizes antigen on MHC I?

It differentiates into a cytotoxic T lymphocyte (CTL) that can kill infected cells by inducing apoptosis.

What happens when a CD4 T cell recognizes antigen on MHC II?

It differentiates into helper T cell subsets (Th1, Th2, Th17, Tfh, or Treg) based on cytokine signals.

What is the difference between naive and effector T cells?

Naive T cells are not yet activated; effector T cells have been activated, differentiated, and are ready to perform their immune functions.

What is the role of CD4+ Th1 cells in immunity?

Activate macrophages, secrete IFN-γ, and promote cell-mediated immunity against intracellular pathogens.

What is the role of CD4+ Th2 cells in immunity?

Activate B cells, promote isotype switching to IgE, and defend against extracellular pathogens (e.g., helminths).

What is the role of CD4+ Th17 cells in immunity?

Secrete IL-17, recruit neutrophils, and promote inflammation against extracellular bacteria and fungi.

What is the role of CD4+ Tfh cells in immunity?

Help B cells in germinal centers; promote isotype switching, affinity maturation, and antibody production.