Immunology Block 1.2: Lymphocyte Development

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Questions and Answers

What is the primary mechanism by which T lymphocytes are selected for maturation in the thymus?

Anergy induction in weakly reactive cells

Proliferation of pre-lymphocytes lacking antigen receptors

Positive selection for recognition of self MHC molecules (correct)

Negative selection for non-self-reactive cells

What is the outcome for immature lymphocytes that fail to express functional antigen receptors during maturation?

They are selected for positive maturation.

They are converted to memory cells.

They undergo clonal expansion.

They undergo apoptosis. (correct)

Which process prevents the development of autoimmune responses by eliminating strongly self-reactive cells?

Allelic exclusion

Negative selection (correct)

Somatic recombination

Clonal selection

In the context of B cell development, what is the result of allelic exclusion?

Expression of a single functional antigen receptor Signup and view all the answers

What is the role of somatic recombination in the formation of unique antigen receptors?

To generate diverse specificity among lymphocyte populations Signup and view all the answers

What is the process by which immature lymphocytes that strongly recognize self antigens are eliminated?

Clonal deletion Signup and view all the answers

During T cell maturation, what is the primary growth factor that influences the expansion of pro-T cells in the thymus?

IL-7 Signup and view all the answers

What mechanism occurs when TCR binds weakly to a self peptide/MHC complex during positive selection?

Clonal expansion Signup and view all the answers

What is the significance of allelic exclusion in T cell development?

To ensure only one TCR type is expressed per T cell Signup and view all the answers

Which of the following best describes clonal anergy in T cells?

Inactive state where T cells do not respond to antigens Signup and view all the answers

What triggers the pre-B cell receptor (pre-BCR) to promote the survival and proliferation of B lineage cells?

The assembly of the µ chain and surrogate light chains Signup and view all the answers

What does allelic exclusion ensure in B lymphocytes?

Only one allele of a gene is expressed Signup and view all the answers

What is the primary consequence for pre-B cells that fail to make the µ protein?

They cannot signal through the pre-BCR and undergo apoptosis Signup and view all the answers

What is anergy in the context of B lymphocytes?

A lack of response to foreign substances Signup and view all the answers

What does clonal deletion primarily entail?

Selective elimination of self-reactive lymphocytes Signup and view all the answers

Which of the following proteins are redirected toward the light chain loci after successful heavy chain rearrangement?

Rag1 and Rag2 Signup and view all the answers

Which process describes the induction of peripheral lymphocyte tolerance through a lack of reactivity?

Anergy Signup and view all the answers

What role do the Ig L genes play in the maturation of B cells after a successful heavy chain rearrangement?

They are rearranged only if the heavy chain fails. Signup and view all the answers

What is the primary environment for B lymphocyte maturation?

Bone marrow Signup and view all the answers

Which process is crucial for generating diverse antigen receptors in lymphocytes?

Rearrangement of immunoglobulin and TCR genes Signup and view all the answers

What does allelic exclusion ensure during B lymphocyte development?

Single specificity of antigen receptors Signup and view all the answers

What is a key outcome of positive selection in T lymphocyte maturation?

Survival of T cells that recognize self-MHC Signup and view all the answers

How do autoreactive B lymphocytes undergo central tolerance during development?

Apoptosis or receptor editing Signup and view all the answers

What occurs to pre-lymphocytes that do not express antigen receptors during maturation?

They die by apoptosis. Signup and view all the answers

What is the process called that generates a diverse array of antigen receptors among lymphocytes?

Somatic recombination Signup and view all the answers

In which selection process are immature T cells selected to recognize self MHC molecules?

Positive selection Signup and view all the answers

What is eliminated during the negative selection of lymphocytes to minimize the risk of autoimmune responses?

Strongly self-reactive B or T cells Signup and view all the answers

What is the primary role of IL-7 in lymphocyte maturation?

To stimulate proliferation of immature lymphocytes Signup and view all the answers

What is the primary purpose of negative selection in T cell maturation?

To eliminate immature lymphocytes that recognize self antigens strongly Signup and view all the answers

During T cell development, what occurs after successful VDJ recombination in pro-T cells?

The TCR β-chain protein is synthesized and expressed Signup and view all the answers

Which of the following best describes the process of positive selection in T lymphocyte maturation?

It promotes survival of T cells that weakly recognize self peptide/MHC complex Signup and view all the answers

What factor produced in the thymus influences the expansion of immature T cell progenitors?

Interleukin-7 (IL-7) Signup and view all the answers

Which statement accurately describes the relationship between self-antigens and T lymphocyte development?

Self-antigens are always present, influencing negative and positive selection Signup and view all the answers

What characterizes the process of clonal deletion in B lymphocytes?

It eliminates B cells that recognize self-antigens. Signup and view all the answers

What is the main function of the pre-B cell receptor (pre-BCR) complex?

To promote B lineage cell survival and proliferation. Signup and view all the answers

Which term describes the process by which only one Ig allele is expressed in lymphocytes?

Allelic exclusion Signup and view all the answers

What occurs after the successful rearrangement of a heavy chain in B cells?

Suppression of light chain gene rearrangement. Signup and view all the answers

Which mechanism allows B cells to continue rearranging Ig light chain genes?

Receptor editing Signup and view all the answers

What best describes anergy in B lymphocytes?

A lack of response to specific antigens, usually self-antigens. Signup and view all the answers

Following what event is Rag1 and Rag2 protein expression turned off in B cells?

Formation of the pre-BCR complex. Signup and view all the answers

Which of the following processes is NOT part of the tolerance mechanisms in the immune system?

Somatic hypermutation Signup and view all the answers

What is the role of VDJ recombinase in antigen receptor gene rearrangement?

To bring gene segments together and cleave DNA Signup and view all the answers

Which gene segments are involved in the rearrangement of Ig heavy-chain and TCR β-chain loci?

V, D, J, and C gene segments Signup and view all the answers

What characterizes combinatorial diversity in lymphocyte antigen receptors?

Different combinations of V, D, and J gene segments Signup and view all the answers

What is the primary purpose of junctional diversity during the VDJ recombination process?

To introduce diversity at the junctions of gene segments Signup and view all the answers

In which type of lymphocytes is VDJ recombinase expressed?

Immature B and T lymphocytes Signup and view all the answers

Which statement is true regarding the rearrangement of TCR genes?

They are exclusive to T lymphocytes Signup and view all the answers

What occurs after the successful rearrangement of a D gene segment with a J segment in B lymphocyte development?

Development into pre-B cells Signup and view all the answers

What is a key distinguishing feature of somatic recombination in lymphocytes?

It involves the use of V, D, and J gene segments Signup and view all the answers

Study Notes

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Lymphocyte Development - CRN No: 15569(Male), 15581 (Female) - Block 1.2 - Subject/Discipline: Immunology

Expert: Dr.Sayed A.Quadri
Block Coordinator: Dr.Sayed A.Quadri
Topic: Lymphocyte Development

Learning Objectives

Explain how diversity develops in the specificity of immunoglobulins and T-cell receptors
Describe how mature B lymphocytes are produced in the bone marrow from common lymphoid progenitor cells
Discuss the role of rearrangement of the membrane immunoglobulin genes in this process
Explain the term "allelic exclusion" and its relevance

Learning Objectives - Maturation and Autoreactive Cells

Explain how the maturation of autoreactive cells is prevented during development of B lymphocytes in bone marrow (central tolerance)
Describe T-lymphocyte production in the thymus, including rearrangement of T-cell receptor genes
Explain how the interaction between TCR and MHC determines the fate of double-positive thymocytes
Detail the difference between positive and negative selection, and how potential threats by autoreactive cells are prevented

Cells of the Immune System

Shows a hierarchical diagram of immune cells branching from stem cells, lymphoid and myeloid progenitors
Illustrates different types of lymphocytes and granulocytes, including B cells, T cells, natural killer cells, neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages, and their relationships.

Development of Immune Repertoires

Early lymphocyte development
Production of diverse antigen receptors
Maturation and selection: B lymphocyte, T lymphocyte

Development of Immune Repertoires - Complex Process

1000 million lymphocyte clones
325 million base pairs of genes
Not enough genes in the human genome to encode every possible receptor
The immune system develops diverse antigen receptors from limited genes, linked to B and T lymphocyte maturation process

Lymphocyte Maturation

B lymphocytes mature in bone marrow.
T lymphocytes mature in the thymus.

Lymphocyte Maturation - Steps

Illustrates the progression from pro-lymphocyte to pre-lymphocyte to immature lymphocyte to mature lymphocyte.

Lymphocyte Maturation - Detailed Steps

Common lymphoid progenitors in bone marrow differentiate into B or T cell progenitors.
Transcription factors are activated for Ig and TCR gene accessibility.
Immature lymphocytes proliferate stimulated by cytokines, predominantly IL-7.
Antigen receptors (ARs) are produced through gene recombination.
Lymphocytes selected for maturation occur at different stages of maturation.

Lymphocyte Maturation - Selection

Lymphocytes are selected at multiple steps during maturation to preserve specificities.
Selection is based on intact antigen receptor expression and recognition.
Cells with functional antigen receptors survive and proliferate.
Pre and immature lymphocytes failing to express receptors die by apoptosis.

Lymphocyte Maturation - Immature T cells

Immature T cells selected in the thymus to recognize self MHC molecules (positive selection).
Ensures complete maturation of cells to recognize antigens displayed by the same MHC molecules on APCs.
Strongly self-reactive B or T cells eliminated to prevent autoimmune responses (negative selection).

Lymphocyte Maturation - Diagram

Illustrations depicts detailed stages of B and T cell development, including checkpoints and selection processes.

Production of Diverse Antigen Receptors

Somatic recombination of AR variable region leads to unique antigen specificities.
Hematopoietic stem cells and early lymphoid progenitors contained multiple V region gene segments, one or few, C region, and D and J genes between V and C genes.
Random selection and recombination of V, D, J gene segments lead to functional genes with unique variable regions (Ig and TCR).
All antigen receptor gene loci = V, J, C genes.
Ig heavy chain and TCR beta chain loci = V, J, C + D gene segments.

VDJ Recombination

Lymphocyte progenitor → B lymphocyte = recombination of first one D gene segment with one J segment, followed by rearrangement of a V segment to the fused D-J element
Somatic recombination occurs with V, D, or J gene segments in immature B and T lymphocytes via VDJ recombinase for efficient processing and expression.
VDJ recombinase expressed only in immature B and T lymphocytes composed of the recombinase-activating gene 1 and 2 (RAG-1 and RAG-2).
Recognizes DNA sequences in antigen receptor V, D, and J gene segments for efficient recombining.

VDJ Recombination - Details

Recombinase brings two Ig or TCR gene segments close together and cleaves DNA.
DNA breaks are repaired by ligases, producing a full-length recombined V-J or V-D-J without intervening DNA segments.
Intact Ig heavy-chain and light-chain genes are rearranged and expressed exclusively in B cells.
TCR alpha and beta genes are rearranged and expressed exclusively in T cells.

VDJ Recombination - Diversity

Combinatorial diversity: different combinations of V, D, and J gene segments produce diverse antigen receptors.
Junctional diversity: changes in nucleotide sequences at the junctions of recombining V, D, and J gene segments increase receptor diversity.

VDJ Recombination - Unlimited Diversity

Junctional diversity is unlimited by three sequence changes removing nucleotides, addition of nucleotides (N-region or P-nucleotides)

Maturation & Selection of B Lymphocytes

Progenitors proliferate pro-B cells.
Cells that generate productive VDJ rearrangements develop into pre-B cells in the cytoplasm.
μ chain and surrogate light chains associate with Igα and Igβ signaling molecules to form the Pre-B cell receptor (pre-BCR) complex.

Maturation & Selection of B Lymphocytes - Pre-BCR

pre-BCR delivers signals to promote survival and proliferation of B lineage cells.
Pre-B cells unable to make productive rearrangements or μ protein fail to express pre-BCR signals and die by apoptosis.

Maturation & Selection of B Lymphocytes (Ig protein stages)

Illustrates stages of B cell development, starting from stem cell to final mature state, showing the evolution of Ig DNA, RNA and Ig expression

Allelic Exclusion

Expressing only one of two Ig alleles
Mechanism: When a functional heavy chain is made the pre-BCR is formed signaling redirecting Rag1 & Rag2 to the Ig light loci, and Rag1 and Rag2 expression turns off once a functional light chain is made.
Interaction with self-antigen: Receptor editing—B cells can continue to rearrange Ig L genes.

Allelic Exclusion - Prevents Unwanted Responses

Only one allele is expressed while the other is silenced in B lymphocytes
Successful heavy-chain gene rearrangement from one chromosome, results in the shutdown of rearrangement of genetic material.

Anergy (Non-responsiveness)

A lack of reaction in the body defense mechanisms to foreign substances
An individual in a state of anergy indicates the immune system is unable to mount a normal immune response against a specific antigen (usually a self-antigen)
A process that induces tolerance to prevent self-destruction (in addition to clonal deletion and immunoregulation)

Clonal Deletion

Elimination of B and T cells expressing receptors for self-antigens before they become immunocompetent.
Responsible for immune tolerance.
Autoreactive T or B cells produced, reacting to body's own proteins (autoantigens) need neutralization prior to circulation to prevent potential attack on healthy tissues.

Maturation & Selection of T Lymphocytes

T cell progenitors migrate from the bone marrow to the thymus.
Immature progenitors (pro-T cells) formed, not expressing CD4 or CD8,
Cells expand in influence of IL-7 production in thymus
Successful VDJ recombination for TCR beta chain protein synthesis
TCR β chain protein is expressed on the surface of protein Pre-Ta to form pre-T cells.

Positive and Negative selection in T cells

Negative selection: Strong interaction resulting in the recognition of self peptide / MHC complexes
Positive selection: Results from a weak interaction resulting in recognition of self-peptide / MHC complexes

Summary - Antigen Receptor Production

Genes for antigen receptors are present in the germline, brought together during lymphocyte maturation.
In B cells, Ig gene segments undergo recombination during maturation in bone marrow.
In T cells, TCR gene segments undergo recombination during maturation in the thymus.

Summary - Specificity Generation & Elimination of Self-Reactive Cells

Receptors of different specificities are generated by different combinations of V, D, and J gene segments.
MHC restriction eliminates immature lymphocytes that strongly recognize self-antigens.

Thank You

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Description

Explore the intricacies of lymphocyte development in this quiz from Block 1.2 of the Immunology course. Focus on key topics such as immunoglobulin diversity, B lymphocyte production, and allelic exclusion. Perfect for students aiming to enhance their understanding of immunological concepts.