T Cell Development and Activation PDF

T cell development and activation Learning Objectives On completion of this session you should be able to 1) Describe the stages of T cell development from hematopoietic stem cells in the bone marrow to mature T cells in the thymus. 2) Recognise positive and negative selection in T cell...

T cell development and activation Learning Objectives On completion of this session you should be able to 1) Describe the stages of T cell development from hematopoietic stem cells in the bone marrow to mature T cells in the thymus. 2) Recognise positive and negative selection in T cell development. 3) Describe the process of T cell activation. 4) Understand T cell-mediated immune responses. T Cell Development 1) T cells develop from stem cells in the bone marrow but complete their maturation in the thymus 2) Thymus comprises lobules containing an outer cortex and inner medulla 3) Stages of development are indicated by the presence/absence of cell surface markers (TCR:CD3, CD4, CD8) Thymus T Cell Development 1) T-cell precursors originate in the bone marrow, but all the important events in their development occur in the thymus 2) T-cell precursors proliferate extensively in the thymus, but most die there 3) Thymocytes then commit along g:d or a:b lineages 4) α:β T cells develop into two distinct functional subsets—CD4 T cells and CD8 T cells 5) This generates T cells that recognise self-MHC (positive selection) and are self-tolerant (negative selection) T Cell Development 1) Positive selection: 2) Occurs in thymic cortex 3) Mediated by thymic cortical epithelial cells that express both MHC class I and II proteins 4) If thymocyte fails to recognise an MHC molecule within 3 - 4 days of initial a:b expression, the cell dies 5) Cortical epithelial cells deliver a survival signal T Cell Development 1) Co-receptor selection: 2) Recognition of an MHC molecule by one co-receptor induces downregulation of the other co-receptor gene 3) Thus, CD4LOW CD8HIGH survive if they recognise MHC class I molecules and CD4HIGH , CD8LOW survive if they recognise MHC class II molecules 4) Mediated cortical epithelial cells that deliver a maturation signal when co-receptor recognition occurs T Cell Development 1) Negative selection: 2) Occurs in thymic cortex and medulla 3) Mediated by cortical epithelial cells and macrophages and dendritic cells 4) If thymocyte recognises self peptide:MHC complex strongly, it dies 5) Different binding affinities to MHC-peptide mediate survival (positive selection) or death (negative selection) 6) Self peptides are derived from thymic proteins and ubiquitous proteins via the blood 7) Thus, cells surviving positive, co-receptor and negative selection are single positive, self tolerant naïve T cells T Cell Activation 1) Recognition of MHC:peptide complex on DCs i.e. antigen recognition 2) Co-stimulatory signal delivered - B7:CD28 3) Cells enter cell cycle (G1) -> proliferation (clonal expansion) 4) Mediated by IL-2 5) IL-2 mediates proliferation & differentiation into effector cells 6) Cytokines expressed by APCs determine the effector cell type the T cell will become T Cell Activation T Cell Mediated Immunity 1) Naive T cells circulate between blood and lymphatics: Blood CD8+ CD4+ T cell T cell Lymphatics + Antigen co-stimulation CD 8+ Tc Cells CD 4+ TH1/TH2/TFH cells 2) Mediated by cell adhesion molecules (CAMs) 3) T cells monitor MHC:peptide complexes on APCs in lymphoid tissue Summary 1. T cell development involves a complex process from hematopoietic stem cells in the bone marrow to mature T cells in the thymus. 2. Positive selection ensures survival of T cells that recognise self- MHC molecules, while negative selection eliminates those with high affinity for self-antigens. 3. T cell activation, triggered by antigen recognition and co- stimulation, leads to differentiation into effector T cell subsets. 4. T cells play pivotal roles in immune defence, combating intracellular pathogens, cancer cells, and infected host cells.