Ontogeny of T and B lymphocytes

Where do the two main stages of lymphocyte development occur?

1. Primary lymphoid organs (bone marrow and thymus) 2. Peripheral (secondary) lymphoid organs.

What is lineage commitment in lymphocyte development?

The decision made by a progenitor cell in the bone marrow to follow either the T or B cell maturation pathway.

Which transcription factor commits progenitor cells to the T-cell lineage?

Activation of Notch-1.

Which transcription factor commits progenitor cells to the B-cell lineage?

Activation of Pax-5.

What are the three main antigen-independent developmental stages?

1. Proliferation 2. Generation of diverse antigen receptors 3. Repertoire selection of immune competent lymphocytes.

What cytokine is essential for T cell proliferation and survival during development?

IL-7, secreted by thymic epithelial cells.

Define receptor diversity and specificity.

Diversity: ability to distinguish among millions of antigens; Specificity: ability to discriminate between antigenic variants.

What does “self-tolerant” mean in lymphocyte development?

Inability of lymphocytes to respond to the body’s own (self) antigens.

List the stages of T-cell development based on CD markers.

Double negative (CD4−CD8−) → Double positive (CD4+CD8+) → Single positive (CD4+ or CD8+).

What is the structure of a B cell receptor (BCR)?

Composed of two light chains and two heavy chains.

What is the structure of a T cell receptor (TCR)?

Composed of two chains: α and β or γ and δ.

What are the two main regions of antigen receptors?

Variable region (binds antigen, determines specificity) and Constant region (responsible for structural and signaling functions).

What is somatic recombination?

A DNA alteration process that generates diversity in B and T cell receptor variable regions by rearranging gene segments (V, D, J).

Which gene segments make up the variable region in heavy (B) or β (T) chains?

V, D, and J segments.

Which gene segments make up the variable region in light (B) or α (T) chains?

V and J segments.

What is the role of RAG1 and RAG2 in receptor development?

They form a nuclease complex that cleaves DNA at selected segments during somatic recombination.

What enzyme adds random nucleotides during receptor junction formation?

Terminal deoxynucleotidyl transferase (TdT).

What enzyme asymmetrically removes nucleotides during recombination?

Endonuclease Artemis.

What does “immune repertoire” refer to?

The total collection of antigen receptor specificities of all T and B cells in an individual.

What is positive selection in T cell development?

Double-positive (CD4+CD8+) thymocytes that bind self-MHC molecules are selected to survive and mature.

What is negative selection in T cell development?

Single-positive T cells that bind too strongly to self-peptide–MHC complexes are eliminated to maintain self-tolerance.

What are the three types of mature lymphocytes?

Naïve, Effector, and Memory lymphocytes.

Describe naïve lymphocytes.

No prior antigen encounter; circulate continuously; unable to perform effector functions.

Describe effector lymphocytes.

Differentiated from activated naïve cells; perform functions that eliminate pathogens; short-lived; migrate to inflammation sites.

Describe memory lymphocytes.

Long-lived cells formed after activation; remain functionally inactive until reactivation; preferentially migrate to non-lymphoid tissues.

What is clonal selection?

The process where an antigen selects specific lymphocytes from the immune repertoire for activation.

What is clonal expansion?

Rapid proliferation of activated lymphocytes producing identical daughter cells (clones).

What are primary immunodeficiencies?

Genetic abnormalities affecting components of the immune system leading to increased infection susceptibility.

Describe Severe Combined Immunodeficiency (SCID).

A group of genetic conditions affecting both T and B cell development, leading to severe recurrent infections.

What defect causes X-linked SCID?

Mutation in molecules essential for T and B cell development (e.g., IL-7 signaling pathway).

What defect causes Omenn’s Syndrome?

Deficiency of RAG1 or RAG2 genes, leading to defective somatic recombination and impaired T/B cell receptor generation.

What is the TREC test used for?

To assess thymic function and T cell production by measuring T cell receptor excision circles.

Why do younger individuals have higher TREC levels?

Because TRECs do not replicate during mitosis and thus dilute as T cells proliferate with age.