V(D)J Recombination and TCR Diversity
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Questions and Answers

What types of combinations can occur during V(D)J recombination?

  • Only D-D combinations
  • D-D or D-D-D combinations (correct)
  • V-D-J combinations only
  • D-D-D-D combinations

    • What must occur first during TCR gene recombination?

  • J combines with V
  • D combines with J
  • V combines with D (correct)
  • V combines with J

    • How do T cell receptors (TCR) establish diversity?

  • Exclusively through somatic mutation
  • Only by combining different chain types
  • By mechanisms operating before antigenic stimulation (correct)
  • Through isotype switching and somatic hypermutation

    • What is the role of PD-1 in T cell regulation?

    <p>Inhibits early steps of TCR signaling</p> Signup and view all the answers

    Which mechanism is NOT responsible for diversity in T cells?

    <p>Isotype switching</p> Signup and view all the answers

    When is CTLA-4 expressed on T cells?

    <p>1-2 days after T cell activation</p> Signup and view all the answers

    What is a major difference between TCR genes and Ig genes?

    <p>TCR genes contain only one exon encoding a transmembrane domain</p> Signup and view all the answers

    Which costimulatory molecule competes with CTLA-4 for binding to B7 ligands?

    <p>CD28</p> Signup and view all the answers

    In terms of theoretical TCR repertoire diversity, how does it compare to Ig repertoire?

    <p>The actual diversity is less than theoretical diversity in TCRs</p> Signup and view all the answers

    Which statement is true regarding the expression of PD-1?

    <p>It is induced within hours of T cell activation.</p> Signup and view all the answers

    How does CTLA-4 function as a negative regulator?

    <p>By recruiting inhibitory molecules to the TCR complex</p> Signup and view all the answers

    What is a contributing factor to TCR diversity in place of isotype switching?

    <p>D segments inclusion and combinatorial joining</p> Signup and view all the answers

    What happens to the extra portions during the DJ recombination process?

    <p>They are deleted</p> Signup and view all the answers

    Which molecules are considered negative regulators of T cell activation?

    <p>PD-1 and CTLA-4</p> Signup and view all the answers

    What is the primary function of CD28 on T cells?

    <p>Promotes survival and activation of T cells</p> Signup and view all the answers

    What is the expression pattern of CD28 on T cells?

    <p>Expressed on both naive and activated T cells</p> Signup and view all the answers

    What occurs if TCRβ rearrangement is unsuccessful on both chromosomes in a thymocyte?

    <p>The cell undergoes apoptosis.</p> Signup and view all the answers

    Which of the following statements is true regarding DN4 thymocytes?

    <p>They downregulate expression of CD25, RAG, and TdT.</p> Signup and view all the answers

    What is the primary role of CD4 and CD8 during the DP phase of thymocyte development?

    <p>They direct thymocyte development.</p> Signup and view all the answers

    During the DP phase, what happens to TCRA locus rearrangement?

    <p>It begins after TCRβ rearrangement is successful.</p> Signup and view all the answers

    What is the significance of positive selection in thymocytes?

    <p>It provides a survival signal to thymocytes with appropriate TCR affinity.</p> Signup and view all the answers

    Which of the following best describes iNKT cells?

    <p>They express an invariant TCRα chain.</p> Signup and view all the answers

    What process shapes the TCR repertoire of DP thymocytes?

    <p>Affinity for MHC/peptides encountered in the thymus.</p> Signup and view all the answers

    What happens to thymocytes that recognize self-antigens during central T cell tolerance establishment?

    <p>They are eliminated before leaving the thymus.</p> Signup and view all the answers

    What is the primary reason for the downregulation of effector T cells after the threat has been removed?

    <p>Reduced exposure to survival signals</p> Signup and view all the answers

    Which mechanism does NOT contribute to effector T cell death?

    <p>Memory T cell activation</p> Signup and view all the answers

    How do memory T cells respond differently upon re-exposure to the same pathogen compared to naive T cells?

    <p>They can differentiate faster into effector cells</p> Signup and view all the answers

    What distinguishes effector memory T cells (Tem) from central memory T cells (Tcm)?

    <p>Tem cells have a shorter life span</p> Signup and view all the answers

    What role do inflammatory cytokines such as IL-12 play in effector T cell persistence?

    <p>They sustain the signals for effector T cell survival</p> Signup and view all the answers

    Memory T cells are critical for vaccination because:

    <p>They recognize the same pMHC as naive and effector T cells</p> Signup and view all the answers

    What is the consequence of cytokine withdrawal in effector T cells?

    <p>Decreased ability to survive and function</p> Signup and view all the answers

    Which of the following statements is true about memory T cells?

    <p>Memory T cells are typically in a resting state</p> Signup and view all the answers

    What is the primary function of peripheral tolerance in lymphocytes?

    <p>To maintain tolerance to self-tissues</p> Signup and view all the answers

    What happens to a lymphocyte when it undergoes apoptosis as part of peripheral tolerance?

    <p>It is eliminated from the immune system</p> Signup and view all the answers

    Which of the following best describes the role of immune regulation in peripheral lymphocyte tolerance?

    <p>To regulate the activity of effector cells</p> Signup and view all the answers

    What condition can result from a failure in peripheral tolerance mechanisms?

    <p>Autoimmune diseases</p> Signup and view all the answers

    What occurs when a mature peripheral lymphocyte interacts with its cognate antigen but does not get activated?

    <p>The lymphocyte becomes tolerant</p> Signup and view all the answers

    What is essential for the regulation of immune responses to harmless non-self entities?

    <p>B7 co-stimulatory signals</p> Signup and view all the answers

    How does the immune system usually respond to innocuous non-self antigens?

    <p>By dampening the immune response</p> Signup and view all the answers

    What role does central tolerance in the thymus play concerning lymphocytes?

    <p>It eliminates autoreactive lymphocytes</p> Signup and view all the answers

    Study Notes

    V(D)J Recombination

    • V(D)J recombination is a process that increases the diversity of T cell receptors and antibodies by combining different gene segments
    • The process is similar for both T cell receptors and antibodies
    • The D segment combines with the V segment first
    • The extra portion of the gene is deleted
    • The V region is then connected
    • There can be multiple V and D region genes, and a DJ portion with other pieces attached
    • During V(D)J recombination, D segments can combine in different ways, including D-D, D-D-D, or D-D-D-D combinations.

    TCR Gene Transcription & Protein Assembly

    • Unlike immunoglobulin genes, TCR genes have only one exon that encodes the transmembrane domain
    • After translation, TCR alpha and beta chains or TCR gamma and delta chains form disulfide bonds and associate with the CD3 molecule to form the TCR complex on the cell surface

    TCR Diversity

    • Mechanisms that generate diversity in T cell receptors operate before antigenic stimulation
    • There are four mechanisms:
      • Multiplicity of germline segments
      • Combinatorial diversity
      • Junctional diversity
      • The ab or yS chain pairing
    • The number of V and D gene segments in TCR loci are lower than the corresponding genes in Ig loci, but there are more TCRA J segments than Ig J segments

    Multiplicity and Combinatorial Joining of Germline Gene Segments

    • The actual diversity from combinatorial sources is more limited than the theoretical diversity
    • The variable D segment inclusion compensates for the lost combinatorial diversity
    • TCR beta and delta loci have more D segments than Ig loci, which only allow one D segment to join with the J segment
    • The precursor TCR/CD3 complex initiates signal transduction and is known as the ‘Pre-TCR'

    Maturation to DN4 Stage

    • Thymocytes that fail to successfully rearrange their TCRβ genes on both chromosomes will not rearrange their TCRA genes and will undergo apoptosis
    • Only 10% of DN3 thymocytes successfully rearrange their TCRβ genes, are β-selected and enter the cell cycle

    DN4 Thymocytes

    • DN4 thymocytes are larger than DN3 cells and are located in the subcapsular region of the thymic cortex
    • They contain a functionally rearranged TCRβ gene
    • They downregulate CD25, RAG, and TdT expression
    • They start expressing low levels of CD4 and CD8

    The Double Positive (DP) Phase

    • The double positive phase is dominated by the thymic selection processes that shape the mature αβ T cell repertoire
    • The expression of CD4 and CD8 are upregulated, and they play important roles in thymocyte development
    • DP thymocytes move towards the thymic medulla
    • DP thymocytes receive signals through Pre-TCR for proliferation
    • V(D)J recombination in both TCRA loci starts, and TCRD loci are deleted
    • Newly synthesized TCRα chains combine with TCRβ chains to form complete TCRαβ heterodimers
    • TCRA rearrangement continues on both chromosomes until positive selection delivers a survival signal

    Thymic Selection and Establishment of Central T Cell Tolerance

    • Thymic selection shapes the TCR repertoire of DP thymocytes based on the affinity of TCRs for MHC/peptides encountered in the thymus
    • Central T Cell tolerance eliminates thymocytes with TCRs that recognize self antigens

    Negative Regulation of Signal 2

    • The potentially destructive power of T cells needs to be tightly regulated
    • The TCR and costimulatory signaling pathways are negatively regulated at multiple steps
    • The two most important negative regulators of T cell activation are PD-1 (programmed death-1) and CTLA-4 (cytotoxic T lymphocyte associated molecule 4)

    PD-1 & CTLA-4

    • PD-1 is expressed by T cells, B cells, and some dendritic cells
    • CTLA-4 expression is only found in T cells
    • PD-1 expression is induced on T cells within hours of activation, while the PD-1 ligand on dendritic cell surfaces is induced by inflammatory cytokines
    • PD-1 engagement with TCR sends an inhibitory signal that shuts down the early steps of the TCR signaling pathway

    CTLA-4

    • CTLA-4 expression is not found on the T cell surface until 1-2 days after T cell activation, giving adaptive response time to eliminate the threat before T cell activation is dampened down
    • CTLA-4 competes with CD28 for binding to the B7 costimulatory ligands
    • CTLA-4 has a higher affinity for B7 proteins than CD28, which displaces CD28 and recruits inhibitory molecules to the TCR complex
    • This is an example of feedback inhibition, a common regulatory feature of the immune system

    Where is CD28?

    • CD28 is expressed on both resting/naive and activated T cells
    • CTLA-4 is virtually undetectable on resting T cells, but is expressed on activated T cells
    • Both CD28 and CTLA-4 are members of the Ig superfamily
    • There are two forms of B7: B7-1 (CD80) and B7-2 (CD86) which are also members of the Ig superfamily
    • B7-1 and B7-2 have similar extracellular domains but differ in their cytoplasmic domains
    • Both B7 molecules are constitutively expressed on dendritic cells

    Termination of Effector T Cell Responses

    • Want to downregulate when not needed
    • Certain molecules do this
    • Th effector cells and CTLs are sustained by signals delivered by inflammatory cytokines and transcription factors
    • After the threats have been removed, there is no further need for their presence
    • Continued exposure to an inflammatory environment without an antigen causes the effector cells to downregulate IL-7R and IL-15R, reducing their ability to receive survival signals
    • Three mechanisms act together to influence the balance of pro-apoptotic/anti-apoptotic gene expression and induce effector cell death:
      • Activation-induced cell death (AICD)
      • Cytokine “withdrawal”
      • T cell clonal exhaustion

    Memory T Cells

    • Memory T cells remember antigens and mount a greater immune response
    • They exist between naive and effector T cells
    • About 5-10% of antigen-specific progeny of T cells generated in a primary response survive AICD or IL-2 withdrawal and become memory T cells
    • The properties of memory T cells are intermediate between naive and effector T cells
    • Memory T cells recognize the same pMHC as naive and effector T cells
    • Memory T cells help with isotype switching
    • The second response is faster and stronger

    Types of Memory T Cells

    • There are two major types of memory T cells:
      • Effector memory T (Tem) cells (shorter life span than Tcm)
      • Central memory T (Tcm) cells
    • These cells have certain properties that differ from each other
    • Tem cells have a shorter life span than Tcm cells in the absence of a specific antigen
    • Tcm cells express high levels of lymph node homing molecules CD62L and CCR7
    • One dose of some vaccines (polio) provides immunity for life.
    • Other vaccines (tetanus) require booster doses every few years to maintain protection

    Lymphocyte Tolerance in the Periphery

    • The adaptive immune responses in peripheral tissues are tightly controlled in two ways:
      • Tolerance: prevents lymphocyte activation.
      • Immune regulation: controls the actions of effector cells
    • Many cells are eliminated during development
    • Central tolerance occurs in the thymus
    • Peripheral tolerance occurs outside of the thymus

    Lymphocyte Tolerance in the Periphery

    • When a mature peripheral lymphocyte interacts with a cognate antigen without activation, tolerance is manifested.
    • In peripheral tolerance, lymphocytes either undergo apoptosis or become functionally inactivated (tolerized).
    • Peripheral self tolerance is vital as it prevents the activation of autoreactive lymphocytes that escaped central tolerance mechanisms.

    Lymphocyte Tolerance in the Periphery

    • Peripheral tolerance exists for harmless, non-self antigens that prevents inflammatory responses from causing unnecessary tissue damage, such as commensal gut microbes, or proteins eaten or inhaled.
    • The regulation of responses to harmless, non-self entities is important for normal health
    • B7 is important for activation
    • Harmful antigens are recognized by the body and danger is sensed, then the second signal can come in
    • The immune system should be downregulated

    Lymphocyte Tolerance in the Periphery

    • The success of both tolerance and regulatory mechanisms ensures that the host’s immune response is directed towards harmful, non-self antigens.
    • Failure to do this can lead to uncontrolled tissue damage and autoimmune diseases.
    • Some lymphocytes may have receptors against self antigens due to their random generation.

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    Description

    This quiz explores the intricate processes of V(D)J recombination that enhance the diversity of T cell receptors and antibodies. It delves into the transcription and assembly of TCR genes, highlighting the mechanisms that contribute to TCR diversity. Test your understanding of these crucial immunological concepts!

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