1Chapter 7: The Development of T Lymphocytes- Both B and T cells undergo gene rearrangement to make antigen receptors, with few differenceso B cells rearrange while still in the bone marrow but T cells leave bone marrow and rearrange in the thymuso There are two distinct T cell lineages: those with α:β receptors and those with γ:δ receptors- Remember: T cells undergo positive and negative selection in the thymus to make sure they aren’t autoreactive (bind too strongly to self-MHC)The development of T cells in the thymus- T cells are lymphocytes that originate in bone marrow and migrate to thymuso Called thymus-dependent lymphocytes  T-cells for short - The two lineages of T-cell develop in a parallel manner from the T-cell precursor, but the α:β cells are much more numerous than the γ:δ cells- While in the thymus, T-cells also begin to express their glycoproteins (CD4 or CD8)7-1 T cells develop in the thymus- The thymus is a primary lymphoid organ located in upper anterior thorax (above heart)o Dedicated to T-cell development; contains thymocytes (immature T-cells)o Thymocytes are embedded in the thymic stroma, which is a network of epithelial cellso The outer portion (cortex) of the thymus is dense and close-packed while the inner portion (medulla) is less dense- Primary organ and not secondary because it deals with production (not application)o Not involved in recirculation; doesn’t receive lympho Blood is the only route (progenitor cells enter and mature T cells leave)- Life of the thymus:o Epithelial cells of cortex come from ectodermal cells; cells of the medulla come from endodermal cellso When just ectothermic and endothermic cells come together, a thymic anlage (rudimentary thymus) is formedo Progenitor cells from bone marrow come in (gives rise to thymocytes and dendritic cells)  dendritic cells concentrate in medullao Macrophages also come in from the bone marrow  concentrated in medulla but scattered in cortexo T-cell progenitors enter thymus at junction between cortex and medulla Differentiate; thymocytes move to cortex and progressively move to inner cortex and medullao Thymus is fully developed before birth, but begins to degenerate by a year after Fat gradually takes over  involution of the thymus- Although the thymus doesn’t produce as many T-cells over time, it doesn’t impair T-cell immunity because an established repertoire is long-lived or can be self-renewing o Different from B-cells; they are short-lived and are constantly being replenishedo Same for thymectomies (removal of thymus)- DiGeorge’s syndrome is experienced by people whose thymus failed to developo T-cells are absento B cells are still made (because these are in bone marrow)o Susceptibility to wide range of opportunistic infections o Similar to SCID7-2 Thymocytes commit to the T-cell lineage before rearranging their T-cell receptor genes- When progenitor cells enter thymus, they aren’t committed to becoming T-cells- They have CD34 and other glycoproteins that are in all stem cells, but don’t express the glycoproteins of T-cells- Once they interact with thymic stromal cells, progenitor cells are signaled to divide and differentiate- After a week or so, they lose their stem-cell markers and are committed (express CD2 and CD5)o Still don’t express anything of T-cell receptor complex (like CD4 or CD8), but they begin to rearrange their T-cell receptor genes2 These are double-negative thymocytes (DN thymocytes) because they don’t express CD4 or CD8- Development wouldn’t happen properly without:o Interleukin-7 (IL-7) Secreted by thymic stromal cells Binds to IL-7 receptor on CD34-expressing progenitor cells Patients who inherit 2 defective alleles of IL-7 don’t have T-cellso Notch 1 Cell-surface receptor on thymocytes Interacts with transmembrane ligands on thymic epithelial cells Generates signals that make sure cells continue along T-cell development pathway and not B-cell development pathway- There are 4 Notch proteins in humans  all regulate by deciding one of two fates Role is analogous to Pax-5 in B-cell development Domain binds to ligand on thymic epithelium  initiates proteolytic cleavage  releases intracellular domain of Notch 1  intracellular domain moves to thymocyte nucleus  becomes part of transcription factor complex  initiates transcription of genes for T-cell development by displacing repressive transcription factors and recruiting activating factors 7-3 The two lineages of T cells arise from a common thymocyte progenitor- α:β cells and γ:δ cells are both derived from the double-negative thymocyte precursor- The genes for the γ, δ, and β chains begin rearranging at the same time (the thymocytes have all of the gene loci; they aren’t restricted to either α:β cells or γ:δ cells)- It’s basically a race!  the γ and δ loci are competing with the β locus to make a functional gene rearrangement and T-cell receptor chain o If the γ and δ loci rearrange first, the cell commits to becoming a γ:δ cello If a functional β chain is made first, it’s incorporated into the pre-T-cell receptor protein This favors but does not commit the cell to become a α:β cell- After the race is completed, gene rearrangement stops and the cell proligerates and expresses CD4 and CD8 co-receptorso The cells at this stage express both co-receptors so they are double-positive thymocytes (DP thymocytes)- At this point, rearrangement of the α locus can happen now or rearrangement of γ:δ genes can continueo More competition!  cell commits to cell type of whichever cell receptor is made first - Most cells won’t make productive T-cell receptor genes (only 2% will be productive)o These cells die by apoptosis and are phagocytosed by macrophages in the thymic cortex7-4 Gene rearrangement in double-negative thymocytes leads to assembly of either a γ:δ receptor or a pre-T-cell receptor- Like immunoglobulins, o T-cell genes can be rearranged productively or nonproductivelyo There are two chances to (two loci)o β and δ loci have V, D, and J segments (D first joins with J and then V joins)o α and γ rearrange once (V and J segments)- Developmental pathway is determined by which genes first rearrange successfully o If γ and δ genes productively rearrange first: γ:δ heterodimer is made and assembles with CD3 signaling complex complex moves to cell surface  signals cell to stop β chain