T Cell Development

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Questions and Answers

Where does early thymocyte development primarily occur?

  • Spleen
  • Thymus cortex
  • Lymph nodes
  • Bone marrow (correct)

What is the primary role of the thymus in T-cell development?

  • Providing a site for B-cell maturation
  • Facilitating T-cell maturation and selection (correct)
  • Filtering the blood to remove pathogens
  • Initiating T-cell production from hematopoietic stem cells

In the thymus, where do T-cell precursors initially begin their development?

  • Cortex (correct)
  • Corticomedullary junction
  • Subcapsular cortex
  • Medulla

Which of the following cell types expresses both CD4 and CD8?

<p>Double positive (DP) cell (D)</p> Signup and view all the answers

What is the significance of positive selection in T-cell development?

<p>Ensuring MHC restriction by selecting T-cells that recognize self-MHC molecules (A)</p> Signup and view all the answers

What is the primary outcome of negative selection in T-cell development?

<p>Elimination of autoreactive T-cells to prevent autoimmunity (C)</p> Signup and view all the answers

Which process leads to the death of most thymocytes during T-cell development?

<p>Death by neglect (C)</p> Signup and view all the answers

What is the ultimate fate of T cells that survive selection in the thymus?

<p>They migrate to the peripheral bloodstream to perform immune functions. (C)</p> Signup and view all the answers

What is the role of the Notch receptor in T-cell development?

<p>Committing cells to the T-cell lineage (D)</p> Signup and view all the answers

In which double negative (DN) stage does TCR rearrangement begin?

<p>DN2 (B)</p> Signup and view all the answers

Which type of T cell is produced as a result of TCR gene recombination in the DN stages?

<p>αβ or γδ T cell (B)</p> Signup and view all the answers

What is the significance of β-selection during T-cell development?

<p>It promotes proliferation and differentiation after successful β chain rearrangement. (C)</p> Signup and view all the answers

Which event is triggered by signals generated after the pre-TCR complex is formed?

<p>Stimulation of CD4 and CD8 coreceptor expression and cell proliferation (A)</p> Signup and view all the answers

What is the outcome of positive selection of a T cell with intermediate affinity for self-MHC molecules?

<p>Differentiation (D)</p> Signup and view all the answers

What is the primary mechanism by which negative selection ensures self-tolerance?

<p>Clonal deletion via apoptosis (C)</p> Signup and view all the answers

Which event characterizes clonal arrest as a form of self-tolerance?

<p>Autoreactive T cells are prevented from maturing further. (D)</p> Signup and view all the answers

What is the primary function of regulatory T cells (TREG) in adaptive immunity?

<p>Quenching or suppressing adaptive immunity (C)</p> Signup and view all the answers

How does apoptosis differ from necrosis?

<p>Apoptosis is a programmed process of cell dismantling, while necrosis results from injury and causes inflammation. (B)</p> Signup and view all the answers

Which of the following is a characteristic feature that distinguishes apoptosis from necrosis at the cellular level?

<p>Chromatin compaction and segregation (A)</p> Signup and view all the answers

What does the instructive model of lineage commitment in T-cell development propose?

<p>TCR/CD4 and TCR/CD8 co-engagement generates unique signals that instruct the T cells which lineage to fully commit to. (C)</p> Signup and view all the answers

According to the kinetic signaling model, what determines whether a T cell commits to the CD4 lineage?

<p>A continuous stimulation signal (C)</p> Signup and view all the answers

A researcher is studying T-cell development and observes a population of cells in the thymus that express neither CD4 nor CD8. Which stage of thymocyte development are these cells most likely in?

<p>Double Negative (DN) (D)</p> Signup and view all the answers

A researcher introduces a mutation in mice that blocks the expression of MHC class II molecules specifically in the thymus. How would this mutation most likely affect T-cell development?

<p>Impaired development of CD4+ T cells (C)</p> Signup and view all the answers

A scientist discovers a new molecule that, when activated, prevents thymocytes with high affinity for self-antigens from undergoing apoptosis. What is the most likely consequence of aberrant activation of this molecule?

<p>Development of autoimmunity (D)</p> Signup and view all the answers

A study reveals that a particular genetic defect results in the failure of pre-TCR formation. Which of the following would be the most direct consequence of this defect?

<p>Inability of thymocytes to progress beyond the DN3 stage (D)</p> Signup and view all the answers

Which model of T-cell lineage commitment suggests that T cells receiving a continuous signal through the TCR commit to the CD4 lineage, whereas an interrupted signal leads to CD8 lineage commitment?

<p>Kinetic signaling model (C)</p> Signup and view all the answers

In a mouse model, researchers discover that thymocytes expressing a specific self-antigen receptor are not deleted in the thymus. However, these T cells are present in the periphery but are unresponsive to stimulation. Which mechanism of self-tolerance is most likely at play?

<p>Clonal anergy (D)</p> Signup and view all the answers

A research team genetically engineers mice to express a modified version of AIRE (AutoImmune REgulator) with enhanced activity. What would be the most likely immunological consequence of this modification?

<p>Enhanced negative selection, leading to a decreased risk of autoimmunity (D)</p> Signup and view all the answers

A researcher is investigating the role of a novel cytokine in T-cell development. They observe that mice lacking this cytokine have a significantly reduced number of double-positive (DP) thymocytes. Which process is most likely affected by the absence of this cytokine?

<p>Survival and proliferation of DP thymocytes (C)</p> Signup and view all the answers

A scientist is studying the process of programmed cell death in thymocytes. They discover a novel protein that inhibits the activity of caspases, enzymes essential for apoptosis. Which of the following outcomes would be the most likely consequence of overexpression of this protein in thymocytes?

<p>Increased survival of autoreactive T cells, leading to heightened risk of autoimmunity (C)</p> Signup and view all the answers

You are analyzing thymocytes in a mouse model with a mutation affecting the gene encoding the pre-TCRα chain. Flow cytometry analysis reveals a significant reduction in cells transitioning from the DN3 to DN4 stage. Which of the following cellular processes directly relies on a functional pre-TCR complex at this developmental juncture?

<p>Allelic exclusion of the T-cell receptor β chain locus (A)</p> Signup and view all the answers

Within the thymic microenvironment, specific interactions dictate the survival and selection of developing T cells. A researcher isolates cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) and performs RNA sequencing to identify unique gene expression profiles. Which of the following gene expression signatures would most accurately differentiate mTECs from cTECs?

<p>Increased expression of autoimmune regulator (AIRE) and tissue-specific antigens (TSAs) (B)</p> Signup and view all the answers

A pharmaceutical company is developing a new drug designed to enhance positive selection in the thymus to improve T-cell immunity in elderly individuals. The proposed mechanism involves increasing the affinity of TCR-MHC interactions without triggering negative selection. Which of the following potential side effects should be of greatest concern during preclinical safety testing?

<p>Development of systemic lupus erythematosus (SLE) due to escape of autoreactive T cells to the periphery (D)</p> Signup and view all the answers

Flashcards

Early Thymocyte Development

Early thymocyte development occurs in the bone marrow, followed by migration to the thymus for further maturation.

T-cell Development in Thymus

T-cell precursors start at the cortex and migrate into the medulla surviving selection.

T Cell Development

Cells migrate to the thymus and undergo various stages of development. Double negative cells lack both CD4 and CD8. Double positive cells express both CD4+ and CD8+.

T Cell Screening

The thymus removes T cells that react to self-antigens. TCR gene segments recombine at the DN stages.

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Thymus Arrival

Early T-cells aren't technically T cells until they commit to the T lineage by interaction with the Notch receptor.

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Thymocyte DN Stages

Thymocytes progress through four double-negative (DN) stages, each differing in the expression of key molecules. TCR rearrangement begins in the DN2 stage.

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TCR Expression

Thymocytes express either TCRαβ (more likely) or TCRγδ receptors.

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Beta-Selection

DN thymocytes undergo β-selection, leading to proliferation/differentiation. A successful β chain pairs with the pre-Tα chain, leading to the DP stage.

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Thymic Selection

DP thymocytes undergo positive selection to ensure MHC restriction and negative selection to ensure self-tolerance.

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Selection Outcomes

Positive selection ensures MHC restriction; cells die by neglect if they cannot bind MHCs. Negative selection ensures self-tolerance by clonal deletion.

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MHC Restriction

The thymus is where thymocytes 'learn' MHC restriction.

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Self-Tolerance Mechanisms

Negative selection ensures self-tolerance by clonal deletion or other mechanisms like clonal arrest, anergy, and editing.

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Kinetic Signaling Model

Cells commit to the CD4 lineage if they receive a continuous signal. Cells commit to CD8 lineage if the stimulation signal is interrupted.

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Apoptosis

Apoptosis: programmed cell death.

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Study Notes

Early Thymocyte Development

  • Very early thymocyte development happens in bone marrow
  • Subsequently, cells migrate to the thymus for further maturation

Development of T Cells in the Thymus

  • Early T-cell precursor development takes place in the bone marrow
  • T-cell precursors start their journey through the cortex of the thymus
  • T-cells that pass selection then move into the medulla
  • Cells migrate to the thymus for further development, going through various stages

T Cell Development Stages in the Thymus

  • Double negative (DN) cells lack both CD4 and CD8
  • Double positive (DP) cells express both CD4+ and CD8+
  • Positive/negative selection leads cells to become single positive for either CD4+ or CD8+
  • Final screening eliminates autoreactive cells
  • Cells are released into the peripheral bloodstream
  • Recombination of TCR gene segments occurs in the DN stages, creating either αβ or γδ T cells

Thymus and T Cell Commitment

  • Cells arriving in the thymus aren't technically T cells yet
  • They can become NK cells, dendritic cells, B cells, and myeloid cells
  • A receptor called Notch commits the cells to the T cell lineage

DN Thymocyte Stages

  • Thymocytes progress through four Double Negative (DN) stages CD4 and CD8
  • Each DN stage has slight differences in molecule expression
  • TCR rearrangement starts in the DN2 stage

TCR Expression

  • Thymocytes can express either TCRαβ or TCRγδ receptors
  • TCRβ rearrangements are among the first to occur
  • TCRαβ outcomes are more likely than TCRγδ

B-Selection

  • DN thymocytes go through β-selection, which leads to proliferation and differentiation
  • A successfully produced β chain pairs with the pre-Tα chain
  • After β-selection, thymocytes are at the DP (CD4 and CD8 double positive) stage
  • Positive/negative selection then occurs, producing a mature SP T cell

Positive and Negative Selection

  • DP thymocytes make up 80% of thymic cells.
  • These cells undergo thymic selection.
  • Positive selection selects thymocytes capable of binding self-MHC molecules, leading to MHC restriction.
  • Negative selection selects against thymocytes with high-affinity receptors for self-MHC/self-peptide complexes, ensuring self-tolerance.
  • The majority of cells, 95%, fail positive selection

MHC Restriction

  • Positive selection ensures MHC restriction
  • Most cells die by neglect before negative selection, due to lack of binding to MHC complexes
  • Cells that successfully bind MHCs shift from the DP to SP stages
  • Thymocytes "learn" MHC restriction in the thymus

Self Tolerance

  • Clonal deletion (induction of apoptosis) eliminates cells with excessively strong anti-self signaling/binding.
  • Autoreactive T cells are prevented from maturing further via Clonal arrest
  • Clonal anergy inactivates autoreactive T cells
  • Clonal editing provides opportunities to rearrange a non-self-reactive TCRα gene

T Cell Lineage Commitment: Models

  • Instructive Model: unique signals are generated from TCR/CD4 and TCR/CD8 co-engagement
  • Stochastic Model: positively selected thymocytes randomly down-regulate either CD4 or CD8
  • Kinetic Signaling Model: cells commit to the CD4 lineage upon receiving a continuous signal, and to the CD8 lineage if the stimulation signal is interrupted

DP Thymocytes

  • DP thymocytes can commit to other kinds of lymphocytes
  • NKT cells: express a TCR with an invariant TCRα chain, and interact with CD1 molecules presenting lipid antigens
  • Intraepithelial Lymphocytes (IELs): usually CD8+, but have features of innate immune cells
  • Regulatory T cells (TREG): CD4+ subset that helps to quell adaptive immunity

Apoptosis

  • Apoptosis is cell death without triggering inflammation
  • Apoptosis constitutes programmed cell death and is a controlled cell dismantling process that does not trigger inflammation
  • Necrosis, conversely, results from injury and releases cell contents, causing inflammation

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