Adaptive Immunity III: T Cell Development

Adaptive Immunity III: Clonal Selection Theory and T Cell Development

• T cell antigen receptor gene loci are arranged in a general germline fashion
• T cell receptors have a specific structure and are expressed on the cell surface
• Positive and negative selection events in the thymus influence T cell receptor repertoire and impose MHC restriction
• MHC molecules exhibit diversity at individual and population levels
• The relationship between the MHC antigen presentation pathway, T cell receptor specificity, and major T cell subsets is described
• Major T cell functions and their relationship to receptor specificity are listed
• The differences between MHC class restriction and allelic restriction for T cells are explained

T Cell Receptor Structure

• The clonotypic receptor is composed of alpha and beta chains, making it monovalent
• The receptor is associated with CD3 signaling molecules, forming a complex
• CD3 is non-polymorphic and found on all T cells
• The complex senses receptor binding and initiates activation signaling

Germ-Line Configuration of T Cell Receptor Genes

• Independent gene rearrangements occur in alpha and beta loci
• Pairing of alpha and beta chains occurs after rearrangements
• Germ-line DNA undergoes recombination to form functional T cell receptors

T Cell Development

• T cell progenitors leave the bone marrow and travel to the thymus, becoming thymocytes.
• Key events in T cell development within the thymus include: gene rearrangement, TCR expression, positive selection (appropriate TCR for host MHC), and negative selection(self-reactive TCR)
• T cells develop through various stages: double-negative, double-positive, and single-positive.

MHC Molecules - Classes, Categories, and Alleles

• MHC molecules are categorized into class I and II
• MHC class I molecules are expressed on all nucleated host cells
• MHC class II molecules are mostly expressed on specialized antigen-presenting cells
• MHC molecules have diverse allelic variants within a population

Effects of Thymic Selection

• Positive selection ensures interaction with self-MHC molecules (MHC restriction)
• T cell subset selection is based on TCR binding to MHC class I (CD8+) or II (CD4+)
• Negative selection deletes autoreactive T cells (self-tolerance)
• The selected T cell repertoire has a narrow range of affinities for self-MHC molecules

What Makes T Cells Work?

• Affinity for self-MHC meets a threshold for selection and survival in the thymus, creating T lymphocytes with receptors specific for the host's MHC alleles
• A diverse T cell receptor repertoire ensures that when a foreign peptide binds to an MHC molecule, the affinity of some T cell receptors will increase above the threshold for activation
• Activation leads to proliferation, differentiation, and acquisition of effector functions

Function of T Cell Matched to Class of MHC Restriction

• MHC class I molecules present endogenous antigens, interacting with CD8+ T cells (cytotoxic T cells)
• MHC class II molecules present exogenous antigens, interacting with CD4+ T cells (helper T cells)
• Different types of CD4+ T cells coordinate the immune response

What Does MHC Restriction Look Like?

• Peptides bind to specialized grooves in MHC molecules.
• Longer grooves in MHC class II bind longer peptides
• T cell receptors recognize peptides and polymorphic residues on MHC molecules

Regulation of Autoreactive B and T Cells not Deleted

• Autoreactive B cells may be denied helper T cell aid leading to B cell anergy
• Autoreactive T cells may not be able to engage specialized APCs,leading to T cell anergy.
• In cases where mechanisms for preventing autoreactivity fail, interventions may sometimes be needed.

Summary

• Naïve T cells leave the thymus expressing CD3, CD4 or CD8 and a T cell receptor
• Selection processes impose MHC restriction and self-tolerance
• T cell expression of CD4 or CD8 defines the class of MHC molecules it recognizes
• T cell functions are associated with the recognized MHC class
• Specialized antigen-presenting cells are vital for naïve T cell activation
• Cell-to-cell contact is essential for activated helper T cells and B cells to produce isotype switching and somatic hypermutation.

Explore the intricate mechanisms of T cell development, including the clonal selection theory and the role of MHC molecules. Learn about T cell receptor structure, selection processes in the thymus, and the functional specificity of major T cell subsets. This quiz delves into important concepts that define adaptive immunity and T cell responses.