1Chapter 5: Antigen Recognition by T Lymphocytes- The sole function of B cells is to produce antibodies but the functions of T cells are more diverse and always involve interactions with other cells- T cell receptors and B cell receptors share some similaritiesSimilarities Differences- Similar structure- Produced as a result of gene rearrangement- Highly variable and diverse in antigen specificity- Each clone expresses single kind of antigen receptor - Binding siteso IGs bind intact molecules (proteins, carbohydrates, and lipids) that are present on bacteria, viruses, parasites, and soluble protein toxinso T cells receptors bind to peptide antigens that come from pathogen’s proteinsT-cell receptor diversity- Membrane-bound glycoprotein that looks like a single arm of IG molecule- Made of 2 different polypeptide chains- One antigen-binding site- No secreted form of T-cell receptor as there is for IGs- There is a variable region (where the antigen binds) and a constant region- Same mechanisms used in B cells and T cells to make variable regions- After T cell is activated (meets with antigen), there is no more change in the structure no somatic hypermutation or isotype switching o This is because T cells are only antigen receptors while B cells are receptors (recognition) and effector molecules5-1 The T-cell receptor resembles a membrane-associated Fab fragment of immunoglobulin - T-cell receptors are made of 2 polypeptide chains: TCRα and TCRβ- Genes encoding the 2 chains have similar germline organization toB cells’ heavy and light chainso Segments have to be rearranged to form a functional gene- α and β chains each have a variable region and constant region- Each chain is folded into protein domainso Amino-terminal V domain, then C domain, then membrane-anchoring domaino Antigen-recognition site is in the Vα and Vβ domains on the CDRs most variable part of molecule Each chain (a and B) has three CDR loops (CDR1, CDR2, and CDR3) which are the loops that are farthestfrom the membrane and are clustered regions of hypervariability- While immunoglobulins have 2 or more binding sites for antigen, T cell receptors only have one binding site forantigen and are only used as cell-surface receptors (never soluble)25-2 T-cell receptor diversity is generated by gene arrangement- Remember: In immunoglobulins, diversity is achieved through mechanisms before and after B cell activationo Before: gene rearrangements V-region sequence diversityo After: changes in mRNA splicing secreted immunolglobulin; C-region RNA rearrangements switch heavy-chain isotype; somatic hypermutation of V-region gene higher affinity (tight binding)- In T cells, the mechanisms are same before; after activation, genes remain unchanged (no mechanisms)o This is because T cells are only for recognition, not for effector functions- Human T cell alpha-chain locus is on chromosome 14 and beta-chain locus is on chromosome 7o Only one Ca gene, two CB genes but no functional differenceo Alpha-chain locus only has V and J segments, beta-chain has V, D, and J segments- Gene rearrangement occurs during T cell development in the thymuso Alpha-chain gene: V segment joined to J segment by somatic DNA recombination V-region sequenceo Beta-chain gene: D joined to J first, then V joinso Similar recombination signal sequences as IG genes and RAG complex, and same enzymes are involved o P and N nucleotides are added during recombination (don’t code for anything) junctional diversity - Severe combined immunodeficiency disorder (SCID)o Occurs when genetic defects result in absence of RAG proteinso B and T lymphocytes are both missingo Bone marrow transplant or other medical intervention is needed- Omenn Syndromeo RAG proteins with partial enzymatic activity are foundo Different symptoms than SCID- After gene rearrangement alpha and beta chains have genes encoding leader peptide, V region, C region, and membrane-spanning regiono Introns are still in there RNA transcript is spliced during transcription introns are removed alpha and beta chains go to the ER they pair to form the α:β T-cell receptor5-3 The RAG genes were key elements in the origin of adaptive immunity - Both T cells and B cells use V(D)J recombination for gene rearrangement - The 2 subunits of RAG recombinase are essential (lacking them leads to SCID and Omenn)- RAG is only made by lymphocytes specific to adaptive immunity- RAG genes are in common ancestor of vertebrates- RAG genes don’t resemble eukaryotic genes, they resemble transposonso Transposons are genetic elements that can make and move copies of itself to different locations on the chromosome o Because they’re so similar, it’s thought that T-cell receptor gene segments originated from insertion of transposon into some type of innate immune receptor gene in ancestor Transposases (characteristic of transposons; enzyme that cuts double-stranded DNA) evolved to encode RAG proteins; terminal repeat sequences (characteristic of transposons; regions of repeating DNA) evolved to become recombination signal sequences- Today, RAG genes are on chromosome 115-4 Expression of the T-cell receptor on the cell surface requires association withadditional proteins - Alpha and beta chains can’t leave ER without help of four invariant membrane proteins- Three of the four are encoded by closely linked genes on chromosome 11 and togetherare called the CD3 complex (CD3γ, CD3δ, and CD3ε)- Fourth one is encoded by gene on chromosome 1 and is called ζ chain- The CD3 proteins, the ζ chain, and the T-cell receptor form the T-cell receptor complex o Once an antigen has been recognized, the CD3 proteins and the ζ chain emit signals tothe interior of the cell because the alpha and beta chains of the T-cell receptor havevery short cytoplasmic tails that don’t signal very wello People lacking CD3δ or CD3ε chains have low numbers of receptors that don’t signaleffectively immunodeficiency35-5 A distinct population of T cells expresses a second class of T-cell receptor with γ and δ chains- Another type of T-cell receptor has γ and δ chains instead of alpha and beta chains (1-5% of the T-cells found in circulation, but they can be the dominant T-cell in epithelial tissue)- T cells express either alpha/beta or γ/ δ; never both- More is known about alpha/beta because they are much more common and plentiful- The two types are very similar but there are
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