UCF PCB 3233 - Chapter 5: Antigen Recognition by T Lymphocytes

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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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UCF PCB 3233 - Chapter 5: Antigen Recognition by T Lymphocytes

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