5_ RECEPTORS.pptx

WELCOME! BMS 545 IMMUNOLOGY SEPTEMBER 27, 2024 ANNOUNCEMENT S  Office Hours  Tuesday 4-5 pm virtual  Thursday 4-5 pm 316J  The ACTUAL last exam material day is 10/7.  FOR THOSE “FOLLOWING” ALONG IN THE TEXTBOOK… I’M GOING OUT OF ORDER  For this Module:  End of Chapter 3...

WELCOME! BMS 545 IMMUNOLOGY SEPTEMBER 27, 2024 ANNOUNCEMENT S  Office Hours  Tuesday 4-5 pm virtual  Thursday 4-5 pm 316J  The ACTUAL last exam material day is 10/7.  FOR THOSE “FOLLOWING” ALONG IN THE TEXTBOOK… I’M GOING OUT OF ORDER  For this Module:  End of Chapter 3 is where all the NK information is- which is included in this module  Chapter 5 is Antigen Recognition by T cells (introduction to TCR & then the MHC/antigen presentation we’ve already covered)  Chapter 7 is The Development of T Lymphocytes  Chapter 8 is T Cell Mediated Immunity  For next Module (B cells):  Chapter 6 is B Cell Development  Chapter 4 is Antibody Development  Chapter 9 Is B Cell & Antibody Mediated Immunity  OBJECTIVES  State where you would expect to find antigen receptors of the adaptive immune system  Describe the structure and organization of the immunoglobulins of the adaptive immune system (BCR, & antibodies, TCR, etc.)  Compare and contrast BCR & TCR  List the components & their functions, of the T Cell Receptor (TCR) complex  Describe the Organization and rearrangement of the T-cell receptor genes to create a final TCR product  Compare & contrast αβ & γδ TCRs (more later too)  Define & use vocab words associated with this lecture (CDR, Fab, TCR etc.)  Know the key chromosomes & segments  SOMATICALLY GENERATED RECEPTORS OF THE ADAPTIVE IMMUNE SYSTEM  Specialized receptors of B-cells & T-cells are created in lymphocytes of each individual through random somatic chromosomal rearrangements & mutations  Result= vast array of receptors specific for precise molecular details found in unique epitopes that may be encountered in future  CELL SURFACE RECEPTOR DIVERSITY  (L) Receptors of the innate immune system (pattern recognition receptors) are limited in number & diversity & are consistent from one normal individual to another  These included the PRRs and complement receptors we already covered in Module 1.  (R) Somatically generated receptors of lymphocytes in the adaptive immune system use random combinations of genes to assemble a very large number of different receptors  We’ll be covering the receptors of the adaptive immune system today, with a focus on the TCRs Chapter Opener Cells infected with mumps virus process viral proteins into peptides that are presented to T  Elements of the Immune System and Their Roles in Defense 1-7 Immunoglobulins (Ig) & T-cell receptors (TCRs) are the antigen receptors of adaptive immunity Comparison of the B-cell receptor (BCR), antibody, & T- cell receptor  B-CELL RECEPTORS  B-cell receptors (BCRs)- cell-surface bound monomeric immunoglobulin associated with disulfide-linked heterodimers called Igα & Igβ 1. BCR binds an epitope 2. Specialized cytoplasmic tails of Igα & Igβ initiate an intracellular signaling cascade that may lead to B-cell activation 3. Some activated B cells terminally differentiate into plasma cells, which secrete immunoglobulins that have the same epitope- binding specificity as their BCR  The secreted immunoglobulins are known as antibodies  IMMUNOGLOBULIN IS BCR (OR TCR) BCR (OR TCR) IS IMMUNOGLOBULIN & ANTIBODY IS SOLUBLE IMMUNOGLOBULIN T-CELL RECEPTORS  T-cell receptors (TCRs) are heterodimers, consisting of either an αβ or a γδ chain pair (an αβ receptor is shown left; γδ receptors have similar structures)  Always membrane bound & recognize antigen combined with MHC molecules  Associated with cluster of differentiation 3 (CD3) complex of transmembrane surface molecules  CD3 complex functions much like Igα & Igβ of BCRs in that it links TCR with intracellular signaling molecules  An additional accessory molecule (CD4 OR CD8) is also present to serve as a type of coreceptor for the TCR* *γδ T cells: Most do NOT have CD4+ or CD8+, in small exceptions do you have CD4+ or CD8+ γδ T cells  Antigen Recognition by T Lymphocytes 5-1 The T-cell receptor resembles a membrane-associated Fab fragment of immunoglobulin “Fragment with Antigen Binding” (Fab)- a proteolytic fragment of IgG that consists of light chain & amino terminal half of heavy chain held together by a disulfide bond between the chains Figure 5.1 The T-cell receptor resembles a membrane-bound Fab fragment  T-cell receptors (TCR)- membrane-bound heterodimer composed of an α chain of 40–50 kDa & a β chain of 35–46 kDa (obviously different if it’s γδ- obviously one chain is γ & one chain is δ).  Extracellular portion of each chain consists of two immunoglobulin- like domains: 1. Domain nearest to the membrane is a constant (C) domain 2. Domain farthest from membrane is a variable (V) domain  α & β chains both span cell membrane & have very short cytoplasmic tails  The 3D structure formed by the 4 immunoglobulin-like domains of TCR resembles the antigen-binding Fab fragment of antibody  “Fragment with Antigen Binding” (Fab)- a proteolytic fragment of IgG that consists of the light chain and the amino terminal half of the heavy chain held together by a disulfide bond between the chains Figure 5.2 Three-dimensional structure of the extracellular part of a T-cell receptor showing the antigen-binding CDR loops  Highly variable Complementarity- determining regions (CDR) loops (numbered 1-3 for each chain), bind pMHC molecule ligand, are arrayed across its relatively flat top surface of TCR  CDR- short region of high diversity in amino acid sequence within the variable region of immunoglobulins & TCR chains  There are 3 CDRs (CDR1, CDR2, CDR3) in each variable region, which collectively contribute to the antigen-binding site & determine antigenic specificity The receptor is  Most variable parts of the variable viewed from domains the side as it would sit on a  AKA “Hypervariable regions (HV)”  Antigen Recognition by T Lymphocytes 5-2 T-cell receptor diversity is generated by gene rearrangement Figure 5.3 Organization and rearrangement of the T-cell receptor genes L, leader sequence  Top & bottom rows show germline arrangement of variable (V), diversity (D), joining (J), & constant (C) gene segments at TCR α-chain & β-chain loci  During T-cell development, a V-region sequence for each chain is assembled by DNA recombination  For α chain (top), rearrangement of a Vα gene segment & a Jα gene segment creates a functional exon encoding the V domain  For β chain (bottom), rearrangement of a Vβ, a Dβ, & a Jβ gene segment creates functional V- domain exon  The assembled genes are transcribed & spliced to produce mRNA (not L, leader sequence shown) encoding α & β chains  Antigen Recognition by T Lymphocytes 5-3 Expression of the T-cell receptor on the T-cell surface requires association with additional proteins Figure 5.4 Polypeptide composition of the T-cell receptor complex  α & β chains bind antigen & form core TCR  This core αβ heterodimer associates with 1 copy each of CD3γ & CD3δ & 2 copies each of CD3ε & the ζ chain  This is necessary for transport of newly synthesized TCR to cell surface & for transduction of signals to cell’s interior after TCR has bound antigen (antigen presentation)  Transmembrane domains of α & β chains contain positively charged amino acids (+), which form strong electrostatic interactions with negatively charged amino acids (–) in transmembrane regions of CD3γ, δ, & ε chains  Antigen Recognition by T Lymphocytes 5-4 A distinctive population of T cells expresses a second class of T- cell receptor with γ and δ chains Although, γδT cells are mainly double- negative for the classical T cell marker CD4 and CD8, small fractions express CD4 or CD8 Figure 5.5 There are two classes of T-cell receptor  αβ T-cell receptor (left) & γδ T-cell receptor (right) have similar structures, but they are encoded by different sets of rearranging gene segments & have different functions V, variable region; C, constant region. Figure 5.6 The organization of the human T-cell receptor γ-chain and δ-chain loci  TCR γ & δ loci (like α & β loci) contain sets of variable (V), diversity (D), joining (J), & constant (C) gene segments  δ locus is located within α-chain locus on chromosome 14, between clusters of Vα & Jα gene segments  There are at least 3 Vδ gene segments, 3 Dδ gene segments, 3 Jδ gene segments, & 1 Cδ gene segment  Vδ segments are interspersed among Vα & other gene segments  This arrangement means that DNA rearrangement within α-chain locus results in deletion of δ-chain locus  The γ locus (chromosome 7) resembles β locus, with 1 set of V segments & 2 C gene segments each with its own set of J segments Figure 5.7 Comparison of the potential diversity in the T-cell receptor repertoire and the B-cell receptor repertoire before encounter with antigen  ALSO A SCIENTIST  Kristel Yee Mon, Ph.D.  PhD Immunology, Weill-Cornell  Studying a rare subset of T cells that may be a biomarker for patient outcome after infection with SARS-CoV2, as well as chemically enhancing innate immune cell types to better prime anti-tumor T cell killer function as a prospective cancer immunotherapy agent  “The reality is that there aren’t that many immunologists who are Black, especially at the faculty level…The small numbers truly speak to the importance of raising awareness of this small but strong community of immunologists who are engaging in excellent work.”  https://news.cornell.edu/stories/2020/11/black- immunology-week-discovery-needs-diversity