Thymocyte Development and Fibroblasts

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Questions and Answers

What cytokines are primarily responsible for the differentiation of Th0 cells into Th1 cells?

IL-4 and IL-5

IFN-gamma and IL-12 (correct)

IL-6 and TNF-alpha

IL-10 and IL-17

Which transcription factor is activated in Th0 cells by cytokines to commit them to the Th2 subset?

STAT4

T-bet

STAT6 (correct)

GATA-3

What is the primary function of IFN-gamma produced by Th1 cells?

To inhibit IL-4 production

To promote Th2 differentiation

To promote inflammation in tissues (correct)

To activate T-bet transcription factor

How do Th2 cells influence Th1 cell differentiation?

By producing cytokines that suppress Th1 population Signup and view all the answers

What type of pathogens primarily trigger the Th2 differentiation pathway?

Extracellular pathogens Signup and view all the answers

Which transcription factor drives Th1 cytokine production?

T-bet Signup and view all the answers

What is the phenomenon called when helper T cell subsets regulate each other?

Cross-regulation Signup and view all the answers

Which of the following best describes the interaction between Th1 and Th2 cells?

Th1 cells inhibit the expansion of Th2 cells. Signup and view all the answers

What initiates Signal 1 for T cell activation?

Binding of pMHC to TCR on naive T cells Signup and view all the answers

What is NOT involved in the activation of T cells via CD3 chains?

Cytokine release from activated B cells Signup and view all the answers

Which structure forms at the T cell and DC interface to facilitate sustained signaling?

Immunological synapse Signup and view all the answers

Which component is found in the inner ring of the immunological synapse?

Central supramolecular activation cluster (cSMAC) Signup and view all the answers

What is required for effective T cell activation beyond a single pMHC engagement?

A sustained interaction for several hours Signup and view all the answers

Which statement about TCRs and pMHC interactions is correct?

Multiple TCR-pMHC interactions lead to activation Signup and view all the answers

What is the role of actin cytoskeleton rearrangement during T cell activation?

To facilitate TCR-pMHC clustering Signup and view all the answers

Which of the following is a key feature of the distal supramolecular activation cluster (dSMAC)?

Primarily consists of actin-based cytoskeletal structures Signup and view all the answers

What happens to autoreactive T cells that encounter high levels of self antigens during embryogenesis?

They proliferate and become exhausted. Signup and view all the answers

What is the consequence for an autoreactive B cell that encounters self antigen without the required Th cell?

It undergoes anergy and dies by apoptosis. Signup and view all the answers

How do autoreactive B cells maintain tolerance in the periphery?

By relying on signals from antigen-specific Th effector cells. Signup and view all the answers

What role do DAMPs and PAMPs play in the activation of autoreactive B cells?

They can delete or anergize autoreactive T cells instead. Signup and view all the answers

What ensures that autoreactive clones that escape central tolerance do not proliferate uncontrollably?

Peripheral tolerance mechanisms. Signup and view all the answers

Which transcription factor is vital for the generation of DN1 thymocytes?

GATA-3 Signup and view all the answers

At which stage do thymocytes commence expression of the CD3 chains?

DN2 Signup and view all the answers

What is the primary function of cTECs in DN1 thymocyte development?

Provide survival signals through c-kit Signup and view all the answers

What occurs during the beta-selection phase for DN3 thymocytes?

Successful rearrangement at the TCR-beta locus Signup and view all the answers

Which component is assembled with the TCR-beta chain to form the pre-TCR?

Pre-TCR-alpha chain Signup and view all the answers

What is the genomic status of TCR genes in DN1 thymocytes?

In germline configuration Signup and view all the answers

Which key event does NOT occur during the DN3 phase of thymocyte development?

Expression of functional TCR-alpha chains Signup and view all the answers

What critical action occurs after a thymocyte successfully passes the pre-TCR checkpoint?

Proliferation and differentiation Signup and view all the answers

What triggers the apoptosis of a target cell by CTLs?

Binding of Fas ligand to FAS Signup and view all the answers

Which cytokines produced by CTLs directly lead to the death of target cells?

TNF and LT Signup and view all the answers

How long does it take for a target cell to succumb to apoptosis after the dissociation of CTL?

3 hours Signup and view all the answers

Which mechanism is NOT involved in the downregulation of effector T cells after threat elimination?

Increased production of IL-7 Signup and view all the answers

What is the primary role of memory T cells during a secondary immune response?

They mount a stronger and quicker response Signup and view all the answers

What happens to effector T cells in the absence of antigen after repeated exposure to inflammatory conditions?

They become downregulated Signup and view all the answers

What percentage of antigen-specific progeny of T cells survive after activation-induced cell death (AICD)?

5-10% Signup and view all the answers

Which factor is crucial for maintaining the presence of effector T cells in the immune response?

Signals from inflammatory cytokines Signup and view all the answers

Study Notes

Thymic Fibroblasts & Thymocyte Development

Thymic fibroblasts secrete extracellular matrix (ECM) components, such as collagen.
Collagen aids in concentrating cytokines necessary for thymocyte development.
Collagen also controls thymocyte adhesion to stromal cells.

DN Stages of T Cell Development

DN1 subset:
- TCR genes are in germline configuration.
- DN1 cells reside in the thymic cortex.
- cTECs provide stem cell factor (SCF), which binds to c-kit on DN1 cells.
- SCF delivers a survival signal to DN1 cells.
- Transcription factor GATA-3 is crucial for DN1 generation.
DN2 subset:
- Also known as Pro-T cells.
- Primarily located in the outer cortex.
- TCR genes remain in germline configuration.
- Expression of CD3 chains begins.
- DN2 thymocytes proliferate rapidly under IL-7 and SCF influence.
DN3 subset:
- DN3 cells stop proliferating and stay in the outer cortex.
- Five key events occur during DN3 stage:
  - Commitment to T cell lineage, generating alpha/beta and gamma/delta T cells.
  - V(D)J recombination commences at TCRG, TCRD, and TCRB loci.
  - Upregulation of RAG and TdT occurs.
  - DN3 cells destined to become alpha/beta T cells express a functional 'Pre-TCR complex'.
  - The complex determines if a functional TCR-beta chain has been produced.
- Successful TCR-beta locus rearrangement halts further rearrangement at TCRG and TCRD loci.
- DN3 thymocytes become early 'pre-T cells' committed to the alpha/beta T cell lineage.
- DN3 cells express a diverse repertoire of TCR-beta chains.
- The TCR-beta locus is the first to undergo VDJ recombination in alpha/beta T cells.
- 'Beta-selection': DN3 thymocytes with successfully arranged TCR-beta chains undergo this process.
- Cells surviving beta-selection pass the pre-TCR checkpoint, leading to DN3 cell proliferation and differentiation.
- Pre-TCR complex formation: A glycoprotein called the 'pre-T-alpha chain' on DN3 cells acts as a surrogate for the real TCR-alpha chain.
- The pre-T-alpha chain assembles with a successfully arranged and translated beta chain, along with CD3 complex proteins.
- The pre-TCR acts as a sensor, initiating signal transduction.

Naive T Cell Activation

Naive T cells enter lymph nodes through HEVs.
They inspect pMHCs displayed by mature DCs near HEVs.
T cells 'crawl' slowly over DC surfaces aided by adhesion molecules, facilitating pMHC screening.
TCRs with sufficient affinity/avidity for pMHCs can activate the T cell.

Signal 1 for T Cell Activation

Signal 1 is delivered when specific pMHCs on DCs bind to multiple TCRs on a naive Th or Tc cell surface.
TCR engagement induces a conformational change in CD3 chains.
This allows phosphorylation of CD3 ITAMs by Lck kinase associated with CD4 and CD8.
Intracellular signaling enzymes are recruited to cytoplasmic tails of CD4, CD8, and CD3 chains.
These enzymes mediate a cascade leading to activation of other enzymes.
Multiple TCR activations result in signal 1.
A single pMHC engagement with TCR is insufficient for complete activation of a naive T cell due to low affinity.
Transient interaction between pMHC-TCR pairs is also insufficient.
Sustained interaction between naive T cell and DC for many hours is needed for optimal T cell activation.
The formation of an immunological synapse between T cell and DC interface is crucial for sustained signaling.
Actin cytoskeletons and polarization occur in both cells, leading to three concentric rings in the immunological synapse:
- Inner ring (cSMAC): Contains aggregated TCRs and costimulatory molecules.
- Middle ring (pSMAC): Contains signaling adaptor talin, integrins, and adhesion molecules.
- Outer ring (dSMAC): Contains actin-based cytoskeletal structures and large proteins.
Some Th subsets promote effector functions against extracellular pathogens.

Th Effector Cell Activation

Most resting Th effectors migrate back to the site of inflammation or tissue containing the antigen after differentiation.
The same antigen that initially activated naive T cells, when presented by an APC, activates Th effectors.
Th effectors then secrete subset-specific panels of cytokines, mediating effector functions.
Th effector cell differentiation pathways are not fixed and can change based on circumstances and transcription program shifts.

Th1 Cells

Intracellular pathogens (viruses and intracellular bacteria) trigger IFN-gamma, IL-12, and IL-27 production by macrophages and DCs.
These cytokines activate STAT4 in Th0 cells, leading to Th1 commitment.
At the site of inflammation or in tissues, Th1 cells are stimulated by antigen, activating transcription factor T-bet.
T-bet drives IFN-gamma production.
Th1 cells oppose Th2 cell differentiation.

Th2 Cells

Extracellular pathogens do not induce IL-12 production by macrophages and DCs.
They stimulate an unknown cell type (possibly mast cells or NKT cells) to secrete IL-4.
IL-4 activates STAT6 in Th0 cells, driving differentiation to Th2 effectors.
At the site of inflammation or in tissues, Th2 cells are stimulated by antigen, activating transcription factor GATA-3.
GATA-3 drives the production of IL-4, IL-5, and IL-13, which are signature Th2 cytokines.
Th2 cells oppose Th1 cell differentiation.

Cross-Regulation of T Helper Subsets

Helper T cell subsets cross-regulate each other.
Their secreted cytokines enhance their own differentiation and expansion while inhibiting other helper T cell lineages.
This is called cross-regulation.
Prominent cross-regulation occurs in the Th1/Th2 and Th17/iTreg pairs.
IL-4 and IL-5 produced by Th2 cells suppress Th1 expansion.
IFN-gamma produced by Th1 cells inhibits Th2 expansion.

Cytotoxic T Lymphocyte (CTL) Effector Functions

Apoptosis induction:
- CTLs kill target cells by expressing FAS ligand (FasL).
- FasL binding to Fas on the target cell induces apoptosis.
Cytotoxic cytokines:
- CTLs produce TNF and LT, which induce apoptosis by binding to TNF receptor 1 on the target cell surface.
IFN-gamma production:
- IFN-gamma produced by CTLs indirectly aids B cells in antibody production, increasing antibody-dependent cell-mediated cytotoxicity (ADCC) and upregulating MHC class I expression.

CTL Dissociation and Re-arming

After delivering a lethal hit, CTLs detach from the damaged target cell within 5-10 minutes due to a low affinity conformation of adhesion molecules.
The target cell undergoes apoptosis within 3 hours of dissociation.
The CTL resumes synthesis of new cytotoxic granules and inspects other host cells.
A single CTL can sequentially attack multiple host cells, delivering lethal hits.
The mechanism preventing CTL self-destruction by its granules remains unknown.

Termination of Effector T Cell Responses

Th effector cells and CTLs are maintained by inflammatory cytokines (IL-12) and transcription factors (ID2 and BCL-3).
After threat removal, effector cells are no longer needed.
Continued exposure to inflammatory environment without antigen causes downregulation of IL-7R and IL-15R, reducing their ability to receive survival signals.
Three mechanisms induce effector cell death:
- Activation-induced cell death (AICD)
- Cytokine withdrawal
- T cell clonal exhaustion

Memory T Cells

Approximately 5-10% of antigen-specific T cell progeny generated in a primary response survive AICD or IL-2 withdrawal.
These cells differentiate into long-lived memory T cells, which are the basis of vaccination.
Memory T cells recognize the same pMHC as naive and effector T cells but have intermediate properties.
Memory T cells are usually found in a resting state but can undergo self-renewal for long-term survival.
Upon reinfection by the same pathogen, memory T cells mount a secondary response faster and stronger than the primary response.
Continuous exposure to an antigen can lead to rapid effector cell proliferation and burnout without memory T cell generation.

Peripheral Tolerance Mechanisms in B Cells

Autoreactive B cells that escape central tolerance are controlled by unique peripheral tolerance mechanisms.
If an autoreactive B cell encounters self-antigen in the periphery, it receives signal 1 but still requires an antigen-specific Th effector cell for signal 2 and 3.
Without the required Th cell (due to central or peripheral tolerance), B cells cannot be activated, even in the presence of DAMPs/PAMPs.
The B cell becomes anergic and undergoes apoptosis within 3-4 days.
This dependence on Th cells for B cell activation minimizes autoreactive responses from Ig gene somatic hypermutation.
Even with an autoreactive Th cell in the periphery, DCs are more likely to delete or anergize the Th cell than activate it in the absence of DAMPS/PAMPs.
An anergic autoreactive Th cell cannot deliver signal 2 to a B cell, causing the B cell to become anergic and undergo apoptosis.

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Description

Explore the essential role of thymic fibroblasts in thymocyte development through extracellular matrix components like collagen. Understand the different DN stages of T cell development, including the specifics of the DN1, DN2, and DN3 subsets.