B and T cell maturation.ppt
- 1. B and T cell Maturation
- 2. • 1st phase: generation of Ag Receptor – V(D)J Gene Rearrangement antigen receptor • 2nd phase: Refinement of Ag Receptor Repertoire – Ag Receptor tested for Ag Recognition – Positive Selection: • for Ag receptor that recognizes “self” Ag weakly – Negative Selection: • for Ag receptor binds strongly to self Ag’s • Cells eliminated via apoptosis • 3rd phase: stimulation by foreign Ag – Clonal Selection of lymphocytes – Generation of effector & memory lymphocytes 1° (central) Lymphoid organs 2° (peripheral) Lymphoid organs B cell Development
- 4. B cell Development in Bone Marrow B cell SC apoptotoic B cells Stromal cell
- 5. Stages in B cell Development • Stem Cell: Ig gene segments in germline DNA • Early Pro-B • Late Pro-B • Large Pre-B • Small Pre-B • Immature B: mIgM • Mature B: mIgM & mIgD Progenitor cell committed to be B cell Rearrangement of H chain Rearrangement of L chain
- 6. T cell Development • Similar to B cells maturation, T cells must undergo numerous steps in the thymus to mature from a TCR negative “pro-T cell” to a mature, circulating T cell. • The antigenic diversity of T cells is reduced during maturation in the thymus by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature. • T cells selection processes include positive and negative selection in the thymus. • Finally functionally distinct mature CD4+ and CD8+ subpopulations that exhibit class II and class I MHC restriction respectively exit thymus.
- 7. Thymus
- 8. T cells precursors do not express TCR, CD3, CD4 and CD8 receptors Changes: •Proliferation of cells. •Changes in cell surface markers •Rearrangement of TCR •+ve and -ve selection
- 9. The Thymus as a Testing Ground for T cells • Within the thymus, the T cells rearrange TCR genes, and are tested for appropriate recognition of self-MHC • Failure to successfully rearrange TCR genes, to pass positive selection, or to pass negative selection results in cell death • Estimated 98% of all thymocytes die by apoptosis in the thymus.
- 11. Positive Selection • Takes place in the CORTEX of the thymus (takes place first) – It is thought that T cells which recognize self-MHC receive a “survival” signal from specialized APCs in the thymus (Thymic Epithelial Cells) and are positively selected. This ensures self-MHC restriction. – Cells that fail positive selection are eliminated within thymus by apoptosis. – During positive selection, gene rearrangement may continue (but MUST STOP after selection).
- 13. Negative Selection • In negative selection,T cells which demonstrate too high an affinity for self MHC molecules alone or self antigen presented by self-MHC are “deleted” in the medulla by Thymic Dendritic Cells. This ensures self-tolerance. • Somehow the Thymic APCs signal apoptosis in reactive cells. At present, it is an open question whether this is the characteristic of the APC or the thymocyte.
- 14. Selection of single positive CD4+ and CD8+ cells • Depending on specificity, Double Positive (DP) T cells (co-expressing CD4 and CD8) will downregulate either CD4 or CD8 to become single positive CD4+ or CD8+ T cells. • The mechanism which regulates this is unknown, but is likely linked to the specificity of the TCR for either Class I or Class II MHC.
- 16. B cell vs. T cell Development 1. Both develop in specialized microenvironments – Bone marrow (B cells) – Thymus (T cells) 2. Production – B cell: production throughout life in BM – T cells: • in thymus at puberty • Adults: – thymus has some residual corticomedullary tissue w/thymocytes – New T cells also generated in “extrathymic” sites – Long-lived peripheral T-cell pool 3. Both have diverse repertoires of Ag Receptors via gene rearrangements
- 17. B vs. T cell Development (cont) 4. Both stages distinguished by surface proteins – B cells: CD45, CD19, CD25, kit, IIL7R, mIg – T cells: CD44, CD25, kit, CD4, CD8, CD3 5. Both Development guided by stromal cells – T cells: development is compartmentalized distinct types of stromal cells - B cells: stromal cells in the bone marrow 6. Both Involve cell death via apoptosis