Maturation and Selection of B and T Cells Notes S24 .pdf

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity III Components of the Adaptive Immune System Maturation and Selection of B and T Lymphocytes Textbook Reading: Chapter 4 (pp. 94 – 99) 2 1 3/14/24 Objectives After completing this module, you should understand the following: Mechanism o...

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity III Components of the Adaptive Immune System Maturation and Selection of B and T Lymphocytes Textbook Reading: Chapter 4 (pp. 94 – 99) 2 1 3/14/24 Objectives After completing this module, you should understand the following: Mechanism of maturation of B cells Mechanism of negative and positive selection of B cells Mechanism of maturation of T cells Mechanism of negative and positive selection of T cells 3 Maturation and Selection of Lymphocytes Maturation and selection of B lymphocytes Maturation and selection of T lymphocytes 4 2 3/14/24 Maturation and Selection of B Lymphocytes Early Steps in B Cell Maturation (pre-B Cells) Maturation of B lymphocytes occurs mainly in the bone marrow Progenitors committed to the B cell lineage proliferate, give rise to a large number of precursors of B cells, called pro-B cells The Ig heavy-chain locus rearranges first, and only cells that are able to make an Ig μ heavy-chain protein are selected to survive and become pre-B cells Some μ protein is expressed on the cell surface in association with two other proteins, called surrogate light chains because they resemble light chains and associate with the μ heavy chain 5 Role of pre-BCR Complex in B Cell Maturation Signals from the pre-BCR complex is the first check point that promote the survival and proliferation of B lineage cells that have made a productive rearrangement at the Ig Hchain locus It selects and expands the pre-B cells that express a functional μ heavy chain (which is an essential component of the pre-BCR and BCR) Pre-B cells that cannot express a pre-BCR or receive pre-BCR signals, die by programmed cell death (apoptosis) 6 3 3/14/24 Completion of B Cell Maturation The IgM-expressing B lymphocyte is the immature B cell The final maturation step involves coexpression of IgD with IgM, which occurs because of the alternatively spliced H chain transcripts The ability of B cells to respond to antigens develops together with the coexpression of IgM and IgD, but the reason is still unknown The IgM+IgD+ cell is the mature B cell, able to respond to antigen in peripheral lymphoid tissues The co-expression of IgD takes place either in the bone marrow or after B cells leave the bone marrow and go to the spleen 7 B Cell Maturation Pro-BCR No recombination Recombined H chain + μ Recombined H and L chain + μ Recombined H and L chain + μ + δ 8 4 3/14/24 Selection of Mature B Cells Positive selection It is based mainly on expression of complete antigen receptors, and not on the recognition specificity of these cells Negative selection If an immature B cell binds a self antigen in the bone marrow, it may reexpress the VDJ recombinase enzyme and undergoes additional light-chain V-J recombination to change its receptor specificity (receptor editing) If B cell is still self reactive after receptor editing, it may die by apoptosis (deletion) 9 Maturation and Selection of Lymphocytes Maturation and selection of B lymphocytes Maturation and selection of T lymphocytes 10 5 3/14/24 Maturation and Selection of T Lymphocytes T cell progenitors migrate from the bone marrow to the thymus for maturation pro-T cells (double-negative thymocytes) do not express CD4 or CD8 and IL-7 produced in the thymus stimulate their proliferation What are CD4 and CD8? 11 CD4 and CD8 There are two subtypes of T-cell Co-receptors CD4 and CD8, which display strong specificity for particular MHC class II and I respectively 12 6 3/14/24 Maturation of T Lymphocytes If V(D)J recombination is successful, TCR β-chain protein is expressed on the cell surface with pre-Tα protein, to form the pre-TCR complex of pre-T cells The pre-TCR complex delivers intracellular signals which promote survival, proliferation, and TCR α gene recombination) Surviving cells express the complete αβ TCR and both the CD4 and CD8 coreceptors (double-positive T cells or double-positive thymocytes) 13 Maturation and Selection Maturation and Selection of T lymphocytes of T Lymphocytes (TCR) β chain is first expressed with pre-Tα protein Expand in number with the help of IL-7 Complete TCR Failure to express antigen receptors at any stage leads to death of the cells by apoptosis 14 7 3/14/24 Positive Selection of T Cells MHC I APC CD4 CD4+ CD8+ MHC II CD8 Double positive T cell 15 Positive Selection of T Cells APC CD4 MHC II CD4+ Recognition of MHCII + weak binding to self MHCII-self peptide complex = positive selection of T cell and loss of CD8 and formation of CD4+ 16 8 3/14/24 Positive Selection of T Cells CD8 MHC I APC CD8+ Recognition of MHCI + weak binding to self MHCI-self peptide complex = positive selection of T cell and loss of CD4 and formation of CD8+ 17 Negative Selection of T Cells CD8 MHC I CD4+ APC CD8+ CD4 Strong binding to self MHC (class I or II)-self peptide complex = apoptosis 18 9 3/14/24 Negative Selection CD8 MHC I CD4+ APC CD8+ CD4 No recognition of self MHC (class I or II) = apoptosis 19 Selection of Mature T Cells Positive Selection T cells whose TCRs moderately interact with class I MHC–peptide complexes preserve the expression of CD8 and lose expression of CD4 Conversely, if a T cell moderately interacts with class II MHC–peptide complexes, this cell maintains expression of CD4 and loses expression of CD8 Negative Selection MHC Restriction T cells that do not recognize an MHC molecule in the thymus die by apoptosis T cells whose TCRs strongly interact with class I or II MHC–peptide will undergo apoptosis T cells recognize and respond to an antigen when it is presented only on a particular self MHC Both positive and negative selection are mediated by recognition of the same set of self MHC–self peptide complexes in the thymus 20 10 3/14/24 Summary Lymphocytes are selected at multiple steps during their maturation to preserve the useful specificities based on the expression of intact antigen receptor components and what they recognize (self or nonself) Many attempts to generate antigen receptors fail because of errors during the gene recombination process The gene rearrangements in the developing lymphocytes randomly generate antigen receptors with highly diverse specificities Immature T cells are selected to survive only if they recognize MHC molecules in the thymus (positive selection). The mechanisms that eliminate strongly self-reactive B and T lymphocytes constitute negative selection 21 Summary The adaptive immune system can distinguish among millions of different antigens or portions of antigens Lymphocytes have extremely diverse specificities due to the expression of of clonally distributed receptors for antigens Total population of lymphocytes consists of many different clones (One cell and its progeny) Each clone expresses an antigen receptor that is different from the receptors of all other clones Clones of lymphocytes specific for different antigens develop before an encounter with theses antigens Each antigen elicits an immune response by selecting and activating a specific clone 22 11