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Transcomplementation can result from the combination in trans of a and b chains encoded by MHC class II genes on different chromosomes. Inter-isotypic molecules also can be formed by a and b chains of two different loci (for example: DR a - DQ b). HLA-DP, -DQ, and –DR (MHC class II) are expressed on APC (classical MHC molecules). HLA-DM and HLA-DN/DO are not, but are involved in the regulation of class II expression: From Dr. Robert Busch’s web site: http://www.stanford.edu/~rbusch/research1.htm “… frequency of naive lymphocytes specific for any given antigen is estimated to be between 1 in 10,000 and 1 in 1,000,000 …” In unimmunized mice: 1 in 26,300 B cells could make anti-SRC IgM no detectable (<1 in a million) B cells that could make anti-SRC IgG (Martínez-Maza, et al. Scandinavian J. Immunol 17:251, 1983) In immunized mice: 1 in 219 B cells could make anti-SRC IgM (5d post-immunization) 1 in 112 B cells could make anti-SRC IgG (12d) 1 in 3,030 B cells could make anti-SRC IgG (180d) (Martínez-Maza, et al. Scandinavian J. Immunol 17:345, 1983) • Ag-activated B cells give rise to germinal centers (GC), zones of proliferating activated B cells: Calame, K. 2001. Plasma cells: finding new light at the end of B cell development . Nature Immunology 2:1103. T CELL DEVELOPMENT AND ACTIVATION • There are a lot of similarities between T and B cells, in their development: – arise from hematopoietic precursors that are generated in the bone marrow – undergo similar DNA rearrangements to generate the genes for their antigen receptor molecules – have the capacity to respond to nearly any antigen – the initial stages of development are antigen-independent, with final differentiation occurring after exposure to antigen – cells that express antigen-receptors that react with self are eliminated • However, there are some significant differences: – since the T cell receptor can interact with antigen only when it is presented in association with self-MHC molecules, T cells need to learn how to bind to a complex of self MHC + Ag peptide – in addition to this (perhaps because of this) T cells do not develop in the bone marrow, they undergo development in a specialized organ, the thymus. • T lymphocytes or T cells got their name from original observations that indicated that they were thymus-derived lymphocytes. • T cell precursors travel from the bone marrow to the thymus: • Following development into mature, antigen-responsive T cells, these T cells emerge from the thymus and migrate to secondary lymphoid tissues, where they interact with antigen, antigen-presenting cells, and other lymphocytes: • The importance of the thymus in T cell development is demonstrated by inherited immune deficiencies: people that do not have a thymus (DiGeorge’s syndrome, aka Thymic Aplasia) do not develop functional T cells. • DiGeorge’s syndrome results from a developmental defect – the failure of the third and fourth pharyngeal pouches to develop, which results not just in thymic defects, but also in absent parathyroids and in aortic arch defects. • Thymectomy early in life reduces the ability to produce T cells. • Thymectomy later in life does not markedly impair T cell number. • In fact, the thymus decreases in size with age. • However, the thymus can still produce new T cells up to middleage, especially in situations where there is loss of T cells (HIV/AIDS). • The thymus is composed of several lobes, each of which has cortical and medullary regions: • The cortex contains immature thymocytes in close contact with thymic epithelial cells. • Medullary areas contain more mature thymocytes, epithelial cells, and dendritic cells and macrophages • While in the thymus, immature T cells, or thymocytes, undergo several changes that allow them to develop into mature T cells, ready for contact with antigen. • Thymocytes interact with thymic epithelial cells and various other cells while in the thymus. • During thymic differentiation, the great majority of thymocytes die by apoptosis, and are ingested by macrophages. • Only a small minority of these T cell progenitors make it out as mature T cells • Thymic development occurs in two phases: 1) production of T cell receptors for antigen, by rearrangement of the TCR genes 2) selection of T cells that can interact effectively with self-MHC • Changes in the expression of cell-surface molecules accompany the thymic differentiation of T cells: – entering thymocytes are TCR, CD3, CD4, and CD8-negative – as thymocytes mature, and undergo rearrangement of their TCR genes to generate a functional TCR, they begin to express CD3, CD4, and CD8 – mature T cells ready to go to the periphery are TCR/CD3+, and either CD4 or CD8 positive Phase 1 of thymic development: rearrangement of TCR genes to produce a functional TCR • Progenitor T cells enter the thymus (sub-capsular region of the outer cortex). • These cells do not have rearranged TCR genes and lack expression of characteristic T cell surface molecules. • Interaction with thymic stromal cells induces these progenitor T cells to proliferate. • These immature thymocytes do not yet express CD4 or CD8, molecules that are expressed by mature T cells: double-negative thymocytes. • There are two types of T cell receptors: gd and ab ab TCR T cells are the most abundant, by far: (or g & d chain) Unlike B cells, in which the genes that encode the BCR rearrange in a set order, the TCR b, g, and d genes start to rearrange at about the same time. If a productive g and d rearrangement occurs first, the T cell is committed to that lineage, and stops further rearrangement of the b TCR gene. However, if b is rearranged first, then the T cell continues to proliferate, and undergoes further rearrangements. This results either in rearranged a TCR gene, yielding an ab TCR lineage cell, or rearranging g and d genes, resulting in a gd TCR cell. • Rearrangements that lead to an ab T cell begin the rearrangement of the b TCR gene. • The first step is DJ joining, followed by VDJ rearrangement. • Expression of b chain stops further b chain rearrangements. b chain is then expressed on the surface of the thymocyte in association with a surrogate a chain (pTa). • Following this, there is rearrangement of the a TCR gene, resulting in a functional a chain, and in the expression of surface TCR, in association with other T cell-associated cell surface molecules. • During this process, a cell that makes an unproductive a chain rearrangement can try again until gets a good a chain, or it exhausts its possibilities: • Thymocytes that have a functional b rearrangement, and express ab or b + the surrogate a chain (pTa) are induced to express both CD4 and CD8 simultaneously – these are called double-positive cells. • Immature T cells that do not undergo a productive rearrangement die by apoptosis. Phase 2 of thymic development: selection of T cells that can interact with self MHC and antigen • This applies only to ab TCR-bearing cells (>95% of T cells). gd T cells are not restricted to interactions with MHC class I or class II molecules • This phase of T cell development consists of two steps: – positive selection (TCR that can interact with self-MHC) – negative selection (eliminate self-reactive cells that are stimulated by MHC + self) Positive Selection • In positive selection, developing thymocytes continue to live if they receive a signal through their TCR. • This signal is mediated by the interactions of these cells with MHC-expressing thymic cortical epithelial cells. • The ~95% of thymocytes that do not receive this signal undergo apoptosis. Positive selection takes place in the cortex of the thymus lobules: • These CD4+ CD8+ TCR+ thymocytes interact with thymic epithelial cells that express both MHC class I and MHC class II molecules, complexed with selfpeptides. • Thymocytes that bind MHC survive; those that don’t die. • TCR a chain rearrangements can continue during positive selection, allowing cells to explore alternative a chains for MHC binding. • Once a T cell is positively selected, TCR rearrangement stops. • The expression of either CD4 or CD8 by a given T cell is determined during positive selection, leading to singlepositive cells (CD4 or CD8-positive). • Those cells that have a TCR that binds to MHC class II end up as CD4 single-positive cells • Those that bind MHC class I as CD8 positive cells: Negative Selection • Thymocytes undergo negative selection in the medullary region: • There, they interact with antigen-presenting cells (dendritic cells, macrophages) that express self-antigens + MHC class I or MHC class II molecules. • Thymocytes that bind to self + MHC too strongly are eliminated as possibly self-reactive cells, and undergo apoptosis. • If self-reactive T cells were allowed to exit the thymus, such cells would mediate autoimmune disease. • Some T cells are reactive with self molecules that are not expressed in the thymus: – such cells can be eliminated in peripheral lymphoid tissues by the induction of anergy – (incomplete stimulation via their TCR) • Some T cells are reactive with self molecules that are not expressed in the thymus: – such cells can be eliminated in peripheral lymphoid tissues by the induction of anergy – (incomplete stimulation via their TCR) anergy or apoptosis X • T cells that exit the thymus have undergone a series of changes that allow them to: – develop a functional TCR – interact with self-MHC – while eliminating self-reactive T cells Antigen-driven T cell Differentiation in Secondary Lymphoid Organs • Mature T cells leave the thymus and migrate to secondary lymphoid tissues (lymph nodes, spleen, mucosa-associated lymphoid tissue), recirculating via the blood and lymph, just like mature B cells do. • Mature T cells are longer lived than mature B cells, and can survive for years without antigenic stimulation. • Unlike B cells, which have just one type of terminallydifferentiated cell (plasma cell), there are various types of effector T cells: – CD8 T cells, which can differentiate into cytotoxic T cells – CD4 T cells, which can become either TH1 or TH2 helper cells.