Class Notes (839,113)
Canada (511,191)
UOIT (1,700)
Biology (294)
BIOL 1010U (101)
Ani (35)
Lecture

IMMUNOLOGY AG RECOGNITION

6 Pages
56 Views

School
UOIT
Department
Biology
Course Code
BIOL 1010U
Professor
Ani

This preview shows pages 1 and half of page 2. Sign up to view the full 6 pages of the document.
Description
IMMUNOLOGY AG RECOGNITION BY T CELLS 1. OVERVIEW -T cells recognize Ag using receptors similar to Ab molecules -TCR receptor diversity generated by V(D)J recombination -Recognizes Ag as a complex associated with MHC (polymorphic) -Optimal Ab response needs B cells and T cells Helper T cells (Th) -activate B cells to make Ab Cytolycic T cells (Tc)- kill infected cells and tumor cells T cells obey the Clonal Selection Theory -Ag receptors distributed on T cells in a clonal fashion, Ag stimulates activation and clonal expansion -T cells do not secrete Ag receptors T cells develop in the thymus, (derived from bone marrow pluripotential hematopoietic stem cells) T cell Recognize native and denatured Ag -T cells see antigenic determinants = short stretches of linear sequence (10 AA) =epitope -Recall: B cell Ab recognize conformational determinants lost in denaturation T cells recognize Ags only on the surface of other cells -T cells don’t recognize free antigen, has to be presented on the surface of APC (ex: macrophage, DC) Proof of Order: AntigenAPC T cells MHC Restriction -T cells from someone for a given Ag cant recognize the Ag on an APC from someone else b/c of MHC -Genetic polymporphism of MHC = different individuals express different MHC alleles -MHC are the major target Ags recognized in graft rejection (Mice = HHumans=HLA) Proteins encoded by MHC (Now wild type = “balance polymorphism” -complex of over 3000 kb of DNA with rich array of genes CLASS HUMAN MOUSE LOCI Composition Expression Example LOCI I ABC KDL α2β2m All cells but A27 (α2 is heavy chain), neurons (β2m on diff. chrom.) II DP, DQ, DR I-E, I-A Αβ B cells K d (heterodimers) Mac, DC Class III = complement proteins and cytokines (soluble serum proteins, C2, C4, factor B) CLASS I CLASS II (Raymond removed the image showing MHC Class I vs Class II composition. See above table.) Note: In murine MHC, class Ib molecules encoded by chrom. Segment telomeric to H2-L 1)Non polymorphic 2)Tissue specific expression Humans CLASS 1b molecules = HLA, E, F, G Note: Class II expression induced in endothelial cells and fibroblasts by cytokine interferon-γ -Variation clustered in class I = α1 and α2 domains class II = α1 and β1 T cell Ag receptor is dual specific, recognizing both Ag and MHC of APC Individual T cells have specificity for particular MHC gene product Locus used depends on (1)functional T cell subset involved(2)Ag being recognized To define which locus is used for a particular T cell 1. Test ability of APCs with MHC to present Ag to Ag-specific T cells -test on various individuals, shared allele will lead to clonal expansion! 2. Use monoclonal Ab specific for distinct MHC encoded products how to make? -Add T cell,, antigen, different Ab = Ab that blocks proliferation means molecule used on surface of APC 2 theories for T cell recognition of Antigen 1. Dual Recognition Model -T cell expressed one receptor for Ag and one for MHC 2. Single Receptor Model -one receptor reads Ag and MHC PROOF: Fusion of 2 T cell lineshybrid T cells (exhibit parental specificity, but not mixed or crossed patterns) Ag and MHC specificity did not behave independently but as a unit Discovery of T cell Ag receptor 1. Generation of monoclonal Ab specific for individual T cell clone (ANTI-IDIOTIPIC AB TO TCR) -Ab recognize unique determinants on the variable regions of TCR  purify receptors at protein level 2. Subtractive hybridization to identify genes uniquely expressed by T cells -look for Ig like that underwent gene rearrangementTCR TCR Structure (like Fab part of IgR) -immunoglobulin gene superfamily, composed of two polypeptide chains α and β linked by a disulfide bond -variable N terminal domain, constant globular domain in a β pleated sheet, membrane D, cytoplasmic D -stabilized by intrachain disulfide bond btw cysteines (Rayond removed the image showing TCR and CD3 chain structure.) -Ag combining site formed by association of variable domains (hypervariable regions) -α/β TCR assembled from gene segments by gene rearrangement β chain = (VDJ + C)  diversity from V(D)J [like IgR heavy chain] α chain = (VJ +C) lacks D [like IgR light chains) Identical rearrangement to Immunoglobulin genes (but initiated in thymus)10 possible TCR structure RAG1/RAG2 : 12-23 spacer role : junctional diversity (N) -but no somatic mutation in hypervariable region, no class switching Differences Btw T and B cell Ag Receptors (1) Univalent (B cell is divalent) (2) Only in membrane firm (BCR can be secreted) (3) Noncovalent attachment with CD3 (invariant, play role in signal transduction) (BCR: Igα and Igβ) (4) Ligand is processed Ag + MHC (Ag ligand is native Ag) CD3 -surface expression used a s a marker for T cells -Ab to CD3 used therapeutically to deplete T cells -minor subset of CD3+ T cells don’t express α/β heterodimer (instead γδ) α/β heterodimer receptor responsible for T cell specificity for both Ag and MHC!!! MECHANISMS OF AG RECOGNITION 1. Ags must be processes prior to recognition -lag time from when Ag is taken up by APC processed and presented Ag to T cell -processing exposes appropriate linear epitopes on MHC -fst macs before lag timeno T cell response afer lag time T cell response -1 specific rxn: Binding of peptide fragment of protein Ag to MHC product on APC Saturated with a valence of 1 2. MHC molecules function as immune response genes Immune response gene=genetic element that controlled response to synthetic immunogen -inherited as a single gene and localized to the H-2 complex on chromosome #17 (mouse) -Only certain peptide fragments of a given protein Ag will bind to a given MHC molecule -Most individuals respond to most protein Ags, b/c proteins usually have some linear AA sequence epitope that can bind to at least one of the several class I or class II MHC molecules expressed by an individual -Some autoimmune diseases correlate with certain HLA alleles! -Many different peptides derived from different protein Ags can potentially bind to given MHC gene product. -variety of peptides can fit into the groove of a given MHC molecule -only certain AA tolerated at key “anchor positions” Ex: HLA-A2 binds nonameric peptides with leucine at position #2 and valine at position #9 -different MHC alleles have different anchor residues Class I = interactions with polar main chain atoms of peptide termini provide binding energy -longer peptides tolerated by bulking in middle 3DStructure= 2 walls of binding site (helix) +floor of binding site (beta sheet) for 9aa Class II = binding site open at either end to allow larger peptides to bind A MODEL FOR AG RECOGNITION BY T CELLS 1.Ag uptake by APC (macrophage) 2 22. Partial Proteolysis of Ag in endocytic compartments
More Less
Unlock Document

Only pages 1 and half of page 2 are available for preview. Some parts have been intentionally blurred.

Unlock Document
You're Reading a Preview

Unlock to view full version

Unlock Document

Log In


OR

Join OneClass

Access over 10 million pages of study
documents for 1.3 million courses.

Sign up

Join to view


OR

By registering, I agree to the Terms and Privacy Policies
Already have an account?
Just a few more details

So we can recommend you notes for your school.

Reset Password

Please enter below the email address you registered with and we will send you a link to reset your password.

Add your courses

Get notes from the top students in your class.


Submit