T Cell Development and Activation

T Cell Development and Activation

• T cells develop from hematopoietic stem cells in the bone marrow, but complete maturation in the thymus.
• The thymus is divided into lobules with a cortex and medulla.
• Development stages are identified by the presence/absence of cell-surface markers (TCR, CD3, CD4, CD8).
• T-cell precursors proliferate extensively in the thymus, and most die there.
• T cells differentiate into two lineages: γ:δ and α:β.
• α:β T cells further distinguish into CD4+ and CD8+ T cells.
• T cells that recognize self-MHC (positive selection) and are self-tolerant (negative selection) are generated.

Learning Objectives

• Describe the stages of T cell development from hematopoietic stem cells in the bone marrow to mature T cells.
• Recognize positive and negative selection in T cell development.
• Describe the process of T cell activation.
• Understand T cell-mediated immune responses.

Positive Selection

• Occurs in the thymic cortex.
• Mediated by thymic cortical epithelial cells expressing MHC class I and II proteins.
• Thymocytes that do not recognize MHC molecules within 3-4 days of α:β expression die.
• Successful recognition by cortical epithelial cells results in a survival signal.

Co-receptor Selection

• Recognition of an MHC molecule by one co-receptor results in downregulation of the other co-receptor gene.
• CD4^lowCD8^high cells survive if they recognize MHC class I molecules.
• CD4^highCD8^low cells survive if they recognize MHC class II molecules.
• Co-receptor recognition by epithelial cells triggers a maturation signal.

Negative Selection

• Occurs in the thymic cortex and medulla.
• Mediated by cortical epithelial cells, macrophages, and dendritic cells.
• Thymocytes that strongly recognize self-peptide:MHC complexes die.
• Different binding affinities to MHC-peptide drive survival or death (positive/negative selection).
• Self-peptides are derived from thymic and ubiquitous blood proteins.
• T cells that successfully complete positive, co-receptor, and negative selection are single positive, self-tolerant, naïve T cells.

T Cell Activation

• Antigen recognition occurs on antigen-presenting cells (APCs) by MHC-peptide complexes.
• Co-stimulatory signals are delivered (e.g., B7:CD28).
• T cells enter the cell cycle (G1) for proliferation, known as clonal expansion.
• Interleukin-2 (IL-2) mediates proliferation and differentiation into effector cells.
• Cytokines expressed by APCs determine the effector T cell type.

T Cell-Mediated Immunity

• Naive T cells circulate between blood and lymphoid tissues.
• Activation occurs via antigen co-stimulation and recognition of MHC-peptide complexes on APCs.
• Cell adhesion molecules (CAMs) mediate the process.
• T cells monitor MHC-peptide complexes within lymphoid tissue.