Adaptive Immunity 3 PDF

Adaptive Immunity III: Clonal Selection Theory and T Cell Development- Objectives Describe the general germ-line arrangement of T cell antigen receptor gene loci Describe general T cell receptor structure and its form of cell surface expression Describe how positive and negative selecti...

Adaptive Immunity III: Clonal Selection Theory and T Cell Development- Objectives Describe the general germ-line arrangement of T cell antigen receptor gene loci Describe general T cell receptor structure and its form of cell surface expression Describe how positive and negative selection events in the thymus shape the T cell antigen receptor repertoire and impose MHC restriction Appreciate the diversity of MHC molecules at the individual and population levels Describe the relationship between MHC antigen presentation pathways, T cell receptor specificity and major T cell subclasses List the major functions of T cells and describe how they relate to receptor specificity Distinguish between MHC class restriction and allelic restriction for T cells  T Cell Receptor Structure Clonotypic receptor is made up of alpha and beta chains. Receptor is monovalent. Together with signaling molecules is referred to the T cell receptor complex. CD3 is non-polymorphic and expressed on ALL T cells. Signaling machinery that senses receptor binding and mediates activation.  Germ-line Configuration of T Cell Receptor Genes a chain locus Independent gene rearrangements at a and b gene loci Pairing of a and b chains b chain locus  T Cell Development T cell progenitor leaves bone marrow and travels to organ called thymus- becomes a thymocyte Key events for T cell development occur in thymus: 1. Gene rearrangement 2. TCR expression 3. Positive selection of TCR appropriate to host MHC 4. Negative selection of self-reactive TCR MHC Molecules- Classes, Categories and Alleles Two classes, 6 categories Co-dominant expression Constellation on cell surface identifies host cell and interacts with T cells Class I on all nucleated host cells Class II mostly on specialized antigen presenting cells, inducible on other cells by pro-inflammatory cytokines eg. Interferon-g Extensive polymorphism with 100s – 1000s of allelic variants in population  Effects of Thymic Selection Positive selection ensures interaction with self-MHC molecules – MHC restriction T cell subset selection-based on TCR binding to MHC class I (CD8+) or II (CD4+) Negative selection deletes autoreactive T cells – self-tolerance Selected repertoire consists of T cell receptors within narrow range of affinities for self MHC molecules Affinity for self-MHC molecules  What Makes T Cells Work? Affinity for self MHC meets threshold for selection and survival in the thymus, creating a set of T lymphocytes with receptors specific for host MHC alleles within class I or II that are expressed by the host. Affinity is below threshold for autoreactivity. Repertoire of T cell receptors selected is diverse enough that when a never seen foreign peptide binds to an MHC molecule, the affinity of some T cell receptor for this peptide/MHC combination will be increased above the threshold for activation. Activation leads to proliferation, differentiation and acquisition of effector functions associated with class of T cell. CD4- helper, MHC class II restricted. CD8- cytotoxic, MHC class I restricted. Function of T Cell Matched to Class of MHC Restriction Some cytokine release Coordination of immune response Recruit cells Activate phagocytic cells Help B cells Activate antigen presentation T cell proliferation What Does MHC Restriction Look Like? Peptide bound in specialized groove of MHC molecule Longer groove in class II, longer peptides bound. T cell receptor distinguishes peptide and polymorphic residues of MHC molecule (allele specificity). Both are required for functional recognition. Regulation of Autoreactive B and T Cells not Deleted Autoreactive B cells denied help from CD4+ T cells Autoreactive T cells engage self-antigens on host cells that aren’t No CD40L-CD40 interaction or cytokines from specialized antigen-presenting cells. No B7-CD28 interaction, activated T cells. No isotype switching or somatic no naïve T cell activation. Anergy ensues. hypermutation. When this fails, non-specific intervention with pharmacological and biological drugs required.  Summary Naïve T cell leaves thymus expressing CD3 (ALL), CD4 OR CD8 and TCR. Selection processes impose MHC restriction (positive section) and self-tolerance (negative selection). Expression of CD4 or CD8 specifies the class of MHC molecule the TCR recognizes. T cell functions associated with class of MHC recognized. Direct effects (killing) and coordinate effects (cytokine release). CD4+ T cell subtypes. Proinflammatory TH1/17, B cell helpers TH2, TfH Treg suppress immunity Specialized antigen-presenting cells required for naïve T cell activation. Cell to cell contact required between activated helper T cell and B cell for isotype switching and somatic hypermutation