Podcast
Questions and Answers
Which component is involved in the interaction with tyrosine kinases during signal transduction in T cells?
Which component is involved in the interaction with tyrosine kinases during signal transduction in T cells?
What is the main role of the CD3 complex in T cell receptor functioning?
What is the main role of the CD3 complex in T cell receptor functioning?
Which region of the TCR V domains does not directly contact the peptide within the pMHC complex?
Which region of the TCR V domains does not directly contact the peptide within the pMHC complex?
What is the consequence of TCR binding to the Ag-MHC complex?
What is the consequence of TCR binding to the Ag-MHC complex?
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What role does the CD3 complex play concerning the surface expression of TCR?
What role does the CD3 complex play concerning the surface expression of TCR?
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Which of the following describes the V domains present in TCRα and TCRβ chains?
Which of the following describes the V domains present in TCRα and TCRβ chains?
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What is indicated about the cytoplasmic tails of TCR chains?
What is indicated about the cytoplasmic tails of TCR chains?
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Which T cell surface molecules serve as coreceptors during antigen recognition?
Which T cell surface molecules serve as coreceptors during antigen recognition?
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What is the primary function of CD4 positive T cells?
What is the primary function of CD4 positive T cells?
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Which statement accurately describes the relationship between CD4, CD8, and TCR interactions with MHC molecules?
Which statement accurately describes the relationship between CD4, CD8, and TCR interactions with MHC molecules?
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What proportion of mature T cells in humans are typically CD4+?
What proportion of mature T cells in humans are typically CD4+?
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What is one of the major functions of CD8 coreceptors?
What is one of the major functions of CD8 coreceptors?
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What is true regarding TCR gene loci in humans?
What is true regarding TCR gene loci in humans?
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Which of the following accurately describes the polypeptide chains of TCRs?
Which of the following accurately describes the polypeptide chains of TCRs?
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What enables CD4 and CD8 coreceptors to stabilize TCR-pMHC binding?
What enables CD4 and CD8 coreceptors to stabilize TCR-pMHC binding?
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What role does Lck play in T cell activation?
What role does Lck play in T cell activation?
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What type of T cells are allowed to mature and exit the thymus?
What type of T cells are allowed to mature and exit the thymus?
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What occurs during positive selection of T cells?
What occurs during positive selection of T cells?
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Where does negative selection primarily take place in the thymus?
Where does negative selection primarily take place in the thymus?
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Which type of thymic APCs is involved in both positive and negative selection?
Which type of thymic APCs is involved in both positive and negative selection?
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What outcome occurs for T cells that fail to pass positive selection?
What outcome occurs for T cells that fail to pass positive selection?
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What role do AIRE+ medullary thymic epithelial cells (mTECs) play in T cell development?
What role do AIRE+ medullary thymic epithelial cells (mTECs) play in T cell development?
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What percentage of developing thymocytes typically survive the selection processes?
What percentage of developing thymocytes typically survive the selection processes?
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What mechanism is primarily responsible for ensuring 'self-tolerance' during T cell maturation?
What mechanism is primarily responsible for ensuring 'self-tolerance' during T cell maturation?
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Which Th cell type is primarily associated with movement to sites of mucosae?
Which Th cell type is primarily associated with movement to sites of mucosae?
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What is a significant difference in the activation of effector Th cells compared to naïve T cells?
What is a significant difference in the activation of effector Th cells compared to naïve T cells?
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Which of the following is NOT a principal type of APC for Th effector cells?
Which of the following is NOT a principal type of APC for Th effector cells?
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How does the level of CD28-B7 costimulation required for effector T cells compare to naïve T cells?
How does the level of CD28-B7 costimulation required for effector T cells compare to naïve T cells?
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Which additional costimulatory pairs are important for the activation of effector T cells?
Which additional costimulatory pairs are important for the activation of effector T cells?
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Which Th cell type is predominantly activated by B cells presenting antigen?
Which Th cell type is predominantly activated by B cells presenting antigen?
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What effect does CD28 signaling have on effector T cells' chemokine receptors?
What effect does CD28 signaling have on effector T cells' chemokine receptors?
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Which T cell type is associated with migration to sites of inflammation?
Which T cell type is associated with migration to sites of inflammation?
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What role does OX40 play in Th1 responses?
What role does OX40 play in Th1 responses?
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What type of superantigen is produced by certain viruses that infect mammalian cells?
What type of superantigen is produced by certain viruses that infect mammalian cells?
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Which cytokine is primarily responsible for driving T and B cell proliferation in Th1 responses?
Which cytokine is primarily responsible for driving T and B cell proliferation in Th1 responses?
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How do superantigens induce T-cell activation?
How do superantigens induce T-cell activation?
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What is a consequence of the overproduction of Th1 cell cytokines?
What is a consequence of the overproduction of Th1 cell cytokines?
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What is NOT a function of Th1 cells?
What is NOT a function of Th1 cells?
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What is the primary function of IFN-g in Th1 responses?
What is the primary function of IFN-g in Th1 responses?
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Which of the following superantigens is NOT derived from bacteria?
Which of the following superantigens is NOT derived from bacteria?
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Study Notes
T Cell Receptor Structure
- TCRs are composed of two chains, α and β, each containing a variable (V) and a constant (C) domain.
- V domains contain four complementarity determining regions (CDRs) involved in peptide-MHC (pMHC) recognition: CDR1, CDR2, CDR3, and HV4.
- HV4 is variable but doesn't directly contact the peptide within the pMHC complex.
- TCRγ and δ chains also contain CDR1, CDR2, CDR3, and HV4 regions.
TCR-CD3 Complex
- The cytoplasmic tails of TCR chains are too short for signal transduction.
- CD3 dimers, analogous to Igα and Igβ chains in B cells, are responsible for signaling through TCR after antigen interaction.
- The CD3 complex comprises three heterodimeric proteins with variable combinations of five ITAM-containing invariant polypeptide chains (epsilon, delta, zeta, eta, and gamma).
CD3 Complex Functions
- Signal transduction: Upon TCR engagement by pMHC, tyrosine residues in the CD3 ITAMs are phosphorylated by Lck, triggering a signaling cascade.
- Surface expression of TCR: CD3 complex associates with TCR in the endoplasmic reticulum (ER) and facilitates its transport to the T cell surface.
CD4 and CD8 Coreceptors
- CD4 and CD8 are coreceptors that bind to conserved regions of MHC class II and class I molecules, respectively.
- Binding is independent of the antigenic peptide recognized by the TCR.
- CD4+ T cells are primarily helper T cells (Th cells), while CD8+ T cells are mostly cytotoxic T cells (CTLs).
- CD4 and CD8 have two main functions:
- Stabilize TCR-pMHC binding.
- Recruit Lck to the TCR-CD3 complex, enhancing TCR-pMHC binding and initiating signal transduction.
TCR Gene Organization
- TCRα, β, γ, and δ polypeptide chains are encoded by TCRA, TCRB, TCRG, and TCRD loci, respectively.
- In both mouse and human, TCRA and TCRD loci are located on chromosome 14, with TCRD nested within TCRA.
T Cell Development in the Thymus
- Similar to immunoglobulin, each TCR chain has a variable (V) and a constant (C) domain.
- TCR V exon is assembled by V(D)J recombination of V, D, and J gene segments in TCRB and TCRD loci.
- The thymus plays a crucial role in selecting for self-MHC-restricted and non-self-reactive T cells (tolerant to self).
- Mature CD4+ and CD8+ T cells, exhibiting class II and class I MHC restriction, respectively, exit the thymus.
Positive Selection
- Occurs in the cortex of the thymus.
- T cells recognizing self-MHC with low or intermediate affinity receive a survival signal from cortical thymic epithelial cells (cTECs).
- Ensures self-MHC restriction.
- Cells failing positive selection undergo apoptosis.
Negative Selection
- Occurs in the medulla of the thymus.
- Also known as central tolerance.
- AIRE+ medullary thymic epithelial cells (mTECs), thymic dendritic cells, and macrophages present self-antigen presented by self-MHC.
- T cells with high affinity for self-MHC or self-antigen are eliminated.
- Ensures self-tolerance.
Activation of Th Effector Cells
- Effector Th cells are activated similarly to naïve T cells but with specific differences.
- Effector Th cells express higher levels of adhesion molecules, facilitating rapid TCR triggering.
- Activation requires significantly lower quantities of antigen/pMHC.
- Less costimulation by APC is required compared to naïve T cells.
Differential Costimulatory Requirements for Th Effector Cells
- While CD28-B7 is the major costimulatory mechanism for naïve T cell activation, effector T cells require only low levels of CD28-B7 costimulation.
- Two additional costimulatory pairs play a role:
- OX40-OX40L: Important in Th1 responses.
- ICOS-ICOSL: Up regulated on Th2 and Th17 cells after activation.
Superantigens
- Bypass normal immune recognition by non-specifically ligating TCR and MHC simultaneously.
- Bind to the Vβ domain of TCR and the α chain of MHC class II.
- Induce T-cell activation and proliferation, but not without costimulation.
- Two types:
- Endogenous superantigens: Cell-membrane proteins encoded by certain viruses, e.g., Mls determinants from mouse mammary tumor virus (MTV).
- Exogenous superantigens: Soluble proteins secreted by bacteria, e.g., exotoxins secreted by Gram-positive bacteria like staphylococcal enterotoxins, toxic-shock syndrome toxin (TSST1), and streptococcal pyrogenic exotoxins.
- T cell activation by superantigens is polyclonal and leads to overproduction of Th-cell cytokines, resulting in systemic toxicity.
Th1 Effector Functions
- Provide help to Tc and B cells.
- Offer cell-mediated and humoral defense against intracellular pathogens.
- Play a role in delayed-type hypersensitivity (DTH), including allergies.
- Secrete cytokines dominated by IL-2, IFN-γ, and lymphotoxin (LT).
- IL-2 drives T and B cell proliferation and enhances reactive oxygen species (ROS) production by macrophages.
- IFN-γ and LT activate macrophages, increase phagocytosis, and upregulate nitric oxide (NO) production.
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Description
Explore the intricate structure of T Cell Receptors (TCRs) and their associated CD3 complex. This quiz will cover the roles of the various domains and the signaling functions that TCRs perform upon interaction with peptide-MHC complexes. Test your understanding of how TCRs contribute to immune response.
