[M4] Topic 1: Lymphocyte Development

Each T cell circulating in the body express

a novel and unique antigen receptor.

Cells entering the thymus are ___ to becoming a lymphocyte and express ___ receptors

not yet committed; no antigen-specific

What type of T cells leave the thymus?

Naive mature T cells.

What do naive mature T cells express?

Unique and specific T cell receptors (TCRs).

What does it mean for a T cell to be MHC restricted?

It is restricted to recognizing antigens presented by self-MHC molecules.

What does it mean for a T cell to be self-tolerant?

It does not respond to self-antigens, preventing autoimmune responses.

Where does T cell development occur?

In the thymus, the primary lymphoid organ located in the chest cavity.

Where does early precursor T-cell development occur?

In the bone marrow.

How do immature T-cell precursors reach the thymus?

They migrate from the bone marrow through the blood and into the thymus.

Where do T-cell precursors first travel upon entering the thymus?

The cortex.

Where do T cells that survive selection migrate to?

The medulla.

What are double negative (DN) thymocytes?

T cells that do not express CD4 or CD8 (CD4-CD8-).

What are double positive (DP) thymocytes?

T cells that express both CD4 and CD8 (CD4+CD8+).

What happens to T cells following positive and negative selection?

They become single positive (SP) and express either CD4 or CD8 (CD4+ or CD8+).

How is T cell development organized within the thymus?

It is organized spatially and temporally.

What is the purpose of screening during T cell development?

To remove autoreactive T cells.

What happens to functional, mature T cells after development?

They are released into circulation.

When does recombination of TCR gene segments occur?

During the double negative (DN) stages.

What are the three main events in early thymocyte development?

Commit to the T-cell lineage.

Initiate V(D)J recombination.

Expand cells with successful T-cell receptor gene rearrangements.

What is positive selection during T cell maturation?

It selects for cells whose T-cell receptors can engage self-MHC.

What is negative selection during T cell maturation?

It eliminates cells whose T-cell receptors bind too strongly to self-peptide/MHC.

What is lineage commitment in T cell development?

It is the commitment of thymocytes to become effector cells, either CD4+ (T helper cells) or CD8+ (Cytotoxic T lymphocytes).

When cells first arrive at the thymus, what types of cells can they potentially become?

NK cells, dendritic cells, or B cells.

What receptor commits cells to the T cell lineage?

Notch receptor.

What are the four DN stages of thymocyte development?

DN1: Migration to thymus.

DN2: TCR beta rearrangement and T-cell lineage commitment.

DN3: Beta-selection.

DN4: Proliferation and TCR alpha rearrangement.

What is one of the first rearrangements to occur in T cell development?

TCR beta (TCRβ) rearrangement.

What is the purpose of beta-selection in DN3 thymocytes?

To ensure successful TCRβ rearrangement, start alpha chain, leading to cell proliferation.

What happens to thymocytes after successful β-selection?

They initiate TCRα chain rearrangement and mature to the double positive (DP) stage.

What stage do thymocytes enter after beta-selection?

The double positive (DP) stage.

What receptors do double positive (DP) thymocytes express?

Both CD4 and CD8 (CD4+CD8+).

What major process must DP thymocytes undergo to become mature single positive T cells?

Positive and negative selection.

What are the possible outcomes of DP thymocytes after selection?

They become mature single positive T cells (CD4+ or CD8+).

What percentage of thymic cells are CD4+CD8+ double positive (DP) thymocytes?

80%

What is the purpose of positive selection in T cell development?

To select thymocytes that can bind self-MHC molecules with low affinity, ensuring MHC restriction.

What is the purpose of negative selection in T cell development?

To eliminate thymocytes with high-affinity receptors for self-MHC/peptide complexes, ensuring self-tolerance.

What is the purpose of positive selection for CD4+CD8+ double positive (DP) thymocytes?

To "learn" MHC restriction in the thymus.

Which cells in the thymus express high levels of MHC class I and II for thymocyte selection?

Cortical thymic epithelial cells (cTEC).

What is the role of cTEC in positive selection?

They present self-peptide/MHC complexes for developing T cells to "browse."

What are the three possible outcomes when T cells encounter self-peptide/MHC complexes?

TCRs can't bind → Death by neglect.

TCRs bind too strongly → Apoptosis.

TCRs bind just right → Positive selection.

What happens to T cells that are positively selected?

They survive and continue their development, maintaining MHC restriction.

What is the primary purpose of positive selection?

To ensure MHC restriction.

What happens to a T cell if its TCR can successfully bind an MHC-peptide complex?

It shifts from double positive (DP) to single positive (SP).

What is the purpose of negative selection?

To ensure self-tolerance.

What happens to thymocytes that show strong anti-self signaling or binding?

They undergo clonal deletion via apoptosis.

What is negative selection also referred to as?

Central tolerance

How does the body delete thymocytes that are reactive to tissue-specific antigens?

Through the action of the Autoimmune Regulator (AIRE) protein.

What is the function of the AIRE protein in the thymus?

It induces the expression of tissue-specific proteins in medullary thymic epithelial cells (mTEC).

How does AIRE recruit transcription factors?

It binds to epigenetic marks on histones to recruit transcription factors.

What are Treg cells?

A subset of CD4+ T cells characterized by the expression of the FoxP3 transcription factor.

What is the primary function of Treg cells?

To negatively regulate immune responses.

How do Treg cells suppress immune responses?

Deplete the local area of stimulating cytokines.

Produce inhibiting cytokines.

Inhibit APC (Antigen-Presenting Cell) activity.

Directly kill T cells.

What is the purpose of peripheral mechanisms of tolerance?

To protect against autoreactive thymocytes that escape negative selection.

How are some self-antigens protected from initiating immune responses?

They are "hidden" because APCs lack the necessary costimulatory molecules.

(e.g. eyes, brain, testes)

How can non-APCs prevent the initiation of autoimmunity?

By presenting self-antigens without triggering an immune response.

What happens when a T cell receives strong self-antigen signaling without costimulation?

It may enter a state of anergy (nonresponsiveness).

What is the purpose of positive selection in B cell development?

To provide survival signals through the completed BCR.

What is the purpose of negative selection in B cell development?

To eliminate auto-reactive B cells.

What is the role of stromal cells in the bone marrow?

They provide support and growth factors to developing cells.

What defines the stages of B cell development?

Cell-surface markers, transcription factor expression, and immunoglobulin gene rearrangements.

What marker is expressed on Pre-Pro B cells?

B220+

Does VDJ recombination occur in Pre-Pro B cells?

No

What major event occurs during the Pro-B cell stage?

V to DJ recombination

What surface marker is expressed on Pro-B cells?

CD19+

What is expressed on the cell surface during the Pre-B cell stage?

IgM

What interleukin receptor is expressed during the Pre-B cell stage?

IL-2R (CD25)

What is the stage following the Pre-B cell in development?

Immature B cell

Where are immature B cells sensitive to tolerance induction?

In the bone marrow.

What surface markers are expressed on immature B cells?

Membrane IgM, B220, CD25, and CD19.

What happens to the BCRs of immature B cells during development?

They are tested against self-antigens.

What is clonal deletion in immature B cells?

Strongly autoreactive cells are eliminated by apoptosis (central tolerance).

What is receptor editing in immature B cells?

Reactivation of light-chain recombination to revise the BCR (central tolerance).

Where do immature B cells migrate for further maturation?

Through the spleen.

What do mature B cells express on their surface?

High levels of IgM and IgD.

Where do mature B cells recirculate?

Between the blood and lymphoid organs.

What is the role of mature B cells in the immune response?

They respond to antigens with T-cell help by producing antibodies.

What is the approximate half-life of mature B cells in the periphery?

Around 4.5 months.

What happens to immature B cells specific for self-antigens in the bone marrow?

They are deleted or made inactive (anergy).

What are three characteristics shared by both B and T cell development pathways?

Rearrangement of gene segments

Screening to avoid self-reactivity

Production of smaller subsets with discrete functions

What are two key differences between B and T cell development?

Location of maturation and screening

Type of screening processes used

What is required for T cell activation following antigen receptor stimulation?

Antigen presentation

What do T cells differentiate into after activation?

Helper or killer (cytotoxic) T cell subsets

What do B cells require for activation?

Help from T cells

What do activated B cells do?

Secrete antibodies