Lymphocyte Development Lecture Notes

Lymphocyte Development Lecture Notes

• Learning Objectives:
  • Explain how diversity develops in the specificity of immunoglobulins and T cell receptors.
  • Describe the production of mature B lymphocytes in the bone marrow from common lymphoid progenitor cells.
  • Discuss the role of membrane immunoglobulin gene rearrangement in this process.
  • Explain the term "allelic exclusion" and its significance.
  • Describe how autoreactive B cell maturation is prevented (central tolerance).
  • Describe T lymphocyte production in the thymus and its involvement with T cell receptor gene rearrangement.
  • Explain how TCR-MHC interaction determines the fate of double-positive thymocytes.
  • Describe positive and negative selection and how they prevent threats from autoreactive cells.

Cells of the Immune System

• A diagram illustrating the development of various immune cells from stem cells, including lymphocytes (B cells and T cells), natural killer cells, and other immune cells.

Gene Expression

• A diagram illustrating the process of gene expression, showing DNA, mRNA, and protein synthesis.

Development of Immune Repertoires

• Early lymphocyte development involves the production of pro-B and pro-T lymphocytes in the bone marrow.
• Lymphocytes will express unique antigen receptors.
• B cells mature in the bone marrow, and T cells mature in the thymus.

Lymphocyte Maturation

• B lymphocytes mature in the bone marrow and T lymphocytes mature in the thymus.
• Multiple stages of maturation, culminating in mature lymphocytes for functional responses toward antigens.
• The development processes involves proliferation and selection processes at various steps along the lymphocyte maturation pathways.

Steps of Lymphocyte Maturation

• Immature stages occur in central lymphoid organs (bone marrow, thymus).
• Pro-lymphocyte, pre-lymphocyte and immature lymphocyte stages.
• Final stage, mature lymphocyte; capable of responding to antigen for functional response.
• Development of antigen receptors is based on gene recombination from germline genes to create functional genes with unique variable regions of antigen receptors.
• The process of gene recombination involves specific enzymes (VDJ recombinase) in different combinations of variable (V), diversity (D) and joining (J) gene segments.

VDJ Recombination- Diversity

• Combinatorial diversity is generated by combining different combinations of V, D, and J segments to build functional antigen receptor genes.
• Junctional diversity provides further diversity by introducing nucleotide changes at the junctions of rearranged segments.
• VDJ recombination is driven by lymphoid specific enzymes for generating diverse antigen receptors.

Allelic Exclusion

• This mechanism ensures that only one of the two alleles (different versions of the gene) is expressed in B lymphocytes.
• This process prevents having multiple antigen specificities in the cell and prevents potentially harmful outcomes.

Anergy and Clonal Deletion

• Anergy is a state of non-responsiveness in lymphocytes, preventing response toward specific antigens, usually a self-antigen, preventing autoimmune responses.
• Clonal deletion is a process by which lymphocytes that recognize self-antigens are eliminated during development (elimination of autoreactive lymphocytes).

T Lymphocyte Maturation

• T cell progenitors migrate from the bone marrow to the thymus for maturation.
• Immature progenitors develop into pro-T cells, which do NOT express CD4 or CD8 proteins.
• The cells expand in the presence of IL-7 from stromal cells in the thymus.
• Successful rearrangement leads to a TCR beta chain, which can be expressed on pre-T cells.

Positive and Negative Selection

• Positive selection selects T cells that can weakly recognize self-MHC molecules, and negative selection eliminates T cells recognizing self-antigens too strongly.
• Self-antigens are constantly present during development.

Summary of Lymphocyte Development

• Gene segments for antigen receptors are initially in germline format and are brought together during maturation of lymphocytes.
• B lymphocytes have immunoglobulin gene segments that recombine in the bone marrow (Ig genes).
• T cells have TCR gene segments that recombine in the thymus.
• These processes create a wide variety of diverse antigen receptors, crucial for targeted immune responses against pathogens.