T cell Development (Immune System - Osmosis)

Immune Response

• Innate immune response is non-specific, but immediate.
• Adaptive immune response is targeted for each invader, but takes time to activate.
• Adaptive immunity has memory, which allows for quicker and stronger responses.

Lymphopoiesis

• Lymphopoiesis produces diverse lymphocytes, each with a unique antigen receptor.
• It eliminates self-reactive lymphocytes to prevent autoimmune diseases.
• Hematopoietic stem cells mature into common lymphoid progenitor cells.
• Common lymphoid progenitors differentiate into B cells and T cells.

B Cell Development

• B cells develop in the bone marrow, maturing in the spleen.

T Cell Development

• T cells mature in the thymus, a fatty organ that shrinks with age, leading to decreased cell-mediated immunity.
• Thymus has an outer cortex and inner medulla.
• Epithelial cells and dendritic cells present antigens to developing T cells on MHC molecules.
• T cell receptors (TCR) only bind peptide antigens when presented on MHC molecules.
• TCRs are composed of an alpha chain and a beta chain, each made of V, D, and J gene segments.
• Multiple V, D, and J segments allow for many unique combinations of TCRs.
• T cell development occurs in three stages: Double negative, double positive, and single positive.

Double Negative (DN) Stage

• DN stage cells express neither CD4 nor CD8.
• DN stage progresses through four steps: DN1, DN2, DN3, DN4.
• DN2 cells express Rag-1 and Rag-2 enzymes, which initiate VDJ recombination.
• VDJ recombinase rearranges D-J segments on both chromosomes, with only one chromosome successfully rearranging.
• DN3 cells successfully join D and J segments.
• DN4 cells attach V segments to D-J segments, forming a complete beta chain.

Double Positive (DP) Stage

• DP stage cells express both CD4 and CD8.
• They rearrange the alpha chain while retaining the same beta chain.
• DP cells undergo positive selection, ensuring they recognize MHC molecules.
• Positive selection involves preserving T cells that recognize the individual's own MHC.
• DP cells also undergo negative selection, eliminating self-reactive T cells.
• AIRE (autoimmune regulator gene) allows thymic epithelial cells to express body-wide antigens for negative selection.

Single Positive (SP) Stage

• SP stage cells downregulate either CD4 or CD8.
• CD4 downregulation leads to CD8+ T cells.
• CD8 downregulation leads to CD4+ T cells.
• SP stage cells are naive T cells, ready to encounter antigens in lymph nodes or spleen.
• Mature T cells are released into the periphery, ready to respond to infections.

Summary

• T cell development in the thymus ensures the production of functional T cells that can recognize antigens and respond effectively to infections.
• This process is a complex series of steps, involving gene rearrangement, selection, and maturation, ensuring the generation of a diverse yet safe repertoire of T cells.

RAG1 and RAG2: Key Players in T Cell Development

• RAG1 and RAG2 are crucial enzymes responsible for V(D)J recombination, a process that generates diversity in the T cell receptor (TCR).

• V(D)J recombination rearranges the variable (V), diversity (D), and joining (J) segments of the TCR genes, creating unique receptors.

• This diversity is essential for the adaptive immune system's ability to recognize a vast array of pathogens.

The Double-Negative (DN) Stage

• The DN stage of T cell development involves thymocytes that do not express the co-receptors CD4 or CD8.

• The DN stage is divided into four phases: DN1, DN2, DN3, and DN4.

• RAG1 and RAG2 are most active in the DN2 and DN3 stages, facilitating TCRβ chain recombination.

Key Functions of RAG1 and RAG2

• RAG1 and RAG2 recognize specific DNA sequences flanking the V, D, and J gene segments and introduce double-strand breaks.

• Other proteins repair and recombine these segments to form a functional TCRβ chain.

Checkpoints in T Cell Development

• Successful TCRβ chain recombination, aided by RAG1 and RAG2, is a critical checkpoint at the DN3 stage.

• If recombination is successful, the thymocyte continues development; otherwise, it may undergo apoptosis.