Humoral Immunity: Antigen Recognition by BCR and TCR, Antigen Presentation to T cells PDF

MVI: Molecular Virology and Immunology Course Coordinator: Dr George Krashias * : [email protected] ( : 22392648 10-10-2024 Department of Molecular Virology Adap...

MVI: Molecular Virology and Immunology Course Coordinator: Dr George Krashias * : [email protected] ( : 22392648 10-10-2024 Department of Molecular Virology Adaptive immunity, antigen recognition by B cell and T cell receptors, antigen presentation to T cells Outline The humoral immune response Antigen recognition by B cell and T cell receptors Antigen presentation to T cells Department of Molecular Virology The humoral immune response Responsible for providing protection against pathogens that are present or multiply in the extracellular spaces of the body Department of Molecular Virology B cell activation by helper T cells Antibody responses to protein antigens require antigen-specific T cell help These antigens are unable to induce antibodies in the absence of T cells Thymus-dependent or TD antigens Two signals are required to induce proliferation of B cells and differentiation into antibody-producing plasma cells Some microbial components can directly activate B cells to produce antibodies in the absence of T cells Thymus-independent antigens or TI antigens Department of Molecular Virology Germinal center B cells undergo V-region somatic hypermutation B cells activated by helper T cells and antigen stimulation Somatic hypermutation can result in amino acid replacements in immunoglobulin V regions that affect the fate of the B cells 1St outcome: Mutations generate a BCR that has low or no affinity to the antigen B cells die by apoptosis 2nd outcome: Mutations generate a BCR that has high affinity for the antigen Increases the chance that the B cell will interact with a T cell, and thus of proliferating and surviving Affinity maturation Department of Molecular Virology B cells can undergo class switching There are five main classes or isotypes of immunoglobulins IgM, IgD, IgG, IgE, and IgA Cγ IgG: IgG1, IgG2, IgG3, IgG4 IgA: IgA1 and IgA2 Naïve B cells express IgM and IgD These five classes are distinguished by the type of heavy chain found in the molecule Cδ Different heavy chains denoted by greek letter µ, γ, δ, α, ε. Cμ Production of different classes of antibodies with the same antigen specificity but distinct effector capacities Class switching does not affect the V region Cα Cε but increases the functional diversity of antibodies by replacing the Cµ region in the antibody gene with another heavy chain C region to produce IgG, IgA, or IgE antibodies Department of Molecular Virology B cells can undergo class switching Productive interactions between B cells and helper T cells are essential for class switching to V occur CD40 ligand is of primary importance V Hyper IgM sydrome Activation-induced cytidine deaminase What determines which C-region exon of the five isotypes will associate with a given heavy-chain V V domain exon? Cytokines Department of Molecular Virology The role of cytokines in B cell class switching Much of what is known today about the regulation of class switching by cytokines has come from experiments in vitro in which mouse B cells are exposed to TLR ligands and cytokines Department of Molecular Virology The role of cytokines in B cell class switching Department of Molecular Virology Population of five classes of antibodies in blood Department of Molecular Virology Antibodies: major characteristics IgG is the only isotype that can pass through the placenta Distributed to the blood and tissue Efficiently neutralize and opsonizes pathogens Activates the complement system IgM is found in blood and secreted in pentameric form Very efficient in activating the complement system IgA produced as a dimer or monomer Mainly operates on epithelial surfaces (dimer) Secreted in tears, saliva, sweat, colostrum milk (dimer) Blood and diffusion to extravascular sites (monomer) IgD is present on the surface of B cells IgE can form strong binding with receptors on the surface of mast cells Sensitization of mast cells Blood and extracellular fluid Department of Molecular Virology Antibodies: major characteristics Department of Molecular Virology  Antigen recognition by the B cell receptor (BCR) and T cell receptor (TCR) Department of Molecular Virology The structure of a typical antibody molecule…..more details Antibodies are the secreted form of the B-cell receptor All antibodies are constructed in the same way Two heavy chains or H chains Two light chains or L chains Disulfide bonds held the molecule together Two types of light chains Lambda (λ) Kappa (k) Department of Molecular Virology The structure of a typical antibody molecule…..more details The amino acid sequences of immunoglobulin heavy and light chains reveal two important features of antibody molecules Each chain consists of a series of sequences, each about 110 amino acids long Each of these repeats correspond to a protein domain The light chain is made up of two such immunoglobulin domains and the heavy chains is made up of four such The variability is located in the immunoglobulin domains amino terminal domain of both the heavy and light chains The amino-terminal amino acid sequences VH and VL of the heavy and light chains vary between different antibodies Constant domains (CH and CL) Department of Molecular Virology The structure of a typical antibody molecule…..more details Each immunoglobulin domain is constructed from two β sheets β sheets: a common motif of regular secondary structure in proteins Made up of strands of the polypeptide chain (β strands) packed together Each domain is a barrel-shaped structure in which strands of polypeptide chain (β strands) running in opposite directions pack together to form two β sheets Department of Molecular Virology The interaction of the antibody molecule with specific antigen The V regions of any given antibody molecule differ from those of every other Sequence variability is not distributed evenly throughout the V region but is concentrated in certain segments Hypervariable regions HR1, HR2, HR3 Framework regions show less variability FR1, FR2, FR3, FR4 Department of Molecular Virology The interaction of the antibody molecule with specific antigen Formation of the antigen-binding site The VH and VL immunoglobulin domains are paired in the antibody molecule and the three hypervariable regions from each domain are brought together Creates a single hypervariable site at the tip of each arm of the molecule Department of Molecular Virology T cell receptor: structure The T cell receptor consists of two different polypeptide chains T cell receptor α (TCR α) and β (TCR β) chains linked by a disulfide bond T cell receptor vs antibody Difference, similarities? Department of Molecular Virology T cell receptor: recognition of antigen The T cell receptor recognizes peptides that are presented by MHC molecules MHC I and MHC II MHC I: Formed by two polypeptide chains 4 domains α1 and α2 domains: peptide-binding cleft Bind short peptides of 8-10 amino acids Found in almost all cells MHC II Formed by two polypeptide chains 4 domains α1 and β1 domains: peptide binding cleft Bind peptides of at least 13 amino acids Found mainly on immune cells Department of Molecular Virology  Antigen presentation to T lymphocytes Department of Molecular Virology The generation of T cell receptor ligands The generation of peptides from native proteins is commonly referred to as antigen-processing The display of the peptide by MHC molecule is referred to as antigen presentation How are peptides generated? MHC I and MHC II deliver peptides to the cell surface from two intracellular compartments Department of Molecular Virology Loading of peptides on MHC I molecules Antigens processed into cytosol to generate peptides through the action of a cytosolic protease known as the proteasome Peptides delivered to the endoplasmic reticulum MHC I molecules retained in the ER until they are loaded with a peptide The process of peptide loading involves a number of proteins with chaperone-like functions Department of Molecular Virology Loading of peptides on MHC I molecules Department of Molecular Virology Department of Molecular Virology Many viruses produce immunoevasins that interfere with antigen presentation Department of Molecular Virology Many viruses produce immunoevasins that interfere with antigen presentation Department of Molecular Virology Department of Molecular Virology Loading of peptides on MHC II molecules Antigens processed into peptides within acidified endocytic vesicles are presented by MHC II molecules MHC II molecule also synthesized within the ER MHC II is associated with the MHC II-associated invariant chain (Ii) CLIP: class II-associated invariant-chain peptide HLA-DM is responsible for catalyzing the removal of CLIP and loading of peptides on MHC I molecules Department of Molecular Virology Loading of peptides on MHC II molecules Department of Molecular Virology  Questions? Department of Molecular Virology