Transcript No T cells
T – CELLS PROMOTE B – CELL DIFFERENTIATION ANTIGEN CYTOKINES B -CELL PLASMA CELL ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY WHAT IS THE STRUCTURE OF THE T – CELL RECEPTOR? B and T cell receptors are similar mIg H mIg L TCR Antigen receptor TCR V TCR C TCR = + The -chain variable region is assembled from V – D – J gene segments by recombination – analogous with IgH chain The α-chain variable region is assembled from V – J gene segments by recombination – like in IgL - chain T-SEJT Single binding C site No somatic mutation -chain locus L1 V1 5' LOCATION OF TCR GENES Chr 7 Ln Vn D1 J1 C1 D2 J2 C2 3' -enhancer and δ-chain locus TCR1 = Chr 14 5' 3' -silencer, enhancer L1 Vδ1 L2 Vδ2 L3 Vδ3 Dδ1Dδ2Dδ3Jδ1Jδ2Jδ3 Cδ L4 Vδ4 5' 3' -gene rearrangement results in the elimination of the δ gene -chain locus L1 V1 5' Ln Vn Chr 7 J1 C1 J2 C2 3' Sequence of D genes allows reading in 3 reading frames No strict 12 – 23 rule for δ-genes (DJ and VD recombination) TCR2 = δ The VARIABLE REGIONS OF - AND -CHAINS ARE GENERATED BY SOMATIC RECOMBINATION Recombination of V and J genes can occur after multiple unsuccessful recombination not functional T-CELL Antigen receptor TCR / next funcional V C further functional (no allele exclusion) mRNS 100 -chain 90 80 70 60 -CHAIN 50 40 30 20 NH2 10 0 10 20 30 CDR1 40 50 60 70 80 CDR2 Diszulfid hidak 90 100 110 120 CDR3 COOH 100 90 -chain 80 70 60 V 50 40 CDR1 and CDR2 loops are not hypervariable 30 20 10 0 C NO SOMATIC HYPERMUTATION 10 20 30 CDR1 40 50 60 CDR2 70 80 90 100 110 120 CDR3 Variability of CDR3 is the result of joining variability ESTIMATED VARIABILITY OF IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES GÉNEK/ KAPCSOLÓDÁS IMMUNOGLOBULIN T CELL RECEPTOR H / VARIABLE (V) 65 70 52 ~70 DIVERZITY (D) 27 0 2 0 rare - OFTEN - JOINING (J) 6 5/4 13 61 JOINING + P + N 2 1 2 1 D (3 frame) V GENE PAIRS 3.4x106 5.8x106 JOINING ~3x107 ~2x1011 TOTAL ~1014 SOMATIC HYPERMUTATON 1018 NO T – CELLS PROMOTE B – CELL DIFFERENTIATION ANTIGEN CYTOKINES B -CELL PLASMA CELL ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY HOW T – CELLS RECOGNIZE ANTIGENS? CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION 1. The TCR is not able to interact directly with soluble or cell-bound antigen 2. T-cell activation can be induced by antigen in the presence of acessory cells, only 3. T-cells recognize virus-infected cells ACCESSORY CELL ANTIGEN BINDING NO INTERACTION T-CELL ACTIVATION Antigen receptor B-CELL T-CELL T-LYMPHOCYTES RECOGNIZE VIRUS-INFECTED CELLS T-cells do not interact with virus particles VIrus-infected cell Cytotoxic T-lymphocytes kill virus-infected cells Citotoxic T-cell virus Infected cell Killed virus-infected cell THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976 T - CELLS Virus A Specific for self and virus T T T T T T MOUSE Y Virus B + Y cells T Virus A + Y cells T T MOUSE X Virus A + X cells Virus A + X cells T T The virus infected cell must derive from the same organism as the T cell THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX MHC Mouse Y Thymus removal Mouse X Mouse X (No T cells) HISTOCOMPATIBILITY IS DETERMINED BY GENES OF THE MHC ORGAN REJECTION IS MEDIATED BY T-CELLS CONGENIC MICE SHARE COMMON MHC GENES Mouse Y Mouse X (Y) Mouse Y and the congenic Mouse X(Y) carry an identical MHC gene locus T-cells recognize products of MHC genes as self or non-self If any cell of an individual starts to produce foreign (viral or bacterial) or abnormal (tumor associated) proteins, the T-cells recognize these antigen presenting cells as altered self cells and respond against them THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX AND THE RESPONE TO PROTEIN ANTIGENS Antigen Antigen Mouse Y IMMUNE RESPONSE Mouse X NO IMMUNE RESPONSE The immune response to protein antigens is also dependent on MHC genes Protein antigens are taken up from the environment by phagocytic cells and via MHC proteins present for T-lymphocytes ANTIGEN PRESENTING CELLS Synthesize antigens – endogenous antigens (virus, tumor) Internalize antigens – exogenous antigens (any protein) Degrade protein antigens to peptides – processing Protein – derived peptides are presented by MHC (HLA) membrane proteins – antigen presentation MHC molecules present both self and non-self protein – derived peptides MHC class I molecules are expressed in all nucleated cells MHC class II molecules are expressed by professional antigen presenting cells ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES T Y soluble Ag Native membrane Ag Cell surface MHCpeptide complex Peptide antigen Cell surface peptides No T-cell response APC T-cell response PROFESSIONAL ANTIGEN PRESENTING CELLS Express MHC class I and class II proteins in the cell membrane Express co-stimulatory molecules (CD40, B7) B cells – specialized for soluble proteins, toxins ADAPTIVE Macrophages – extracellular pathogens (bacteria, yeast) Dendritic cells – viruses, apoptotic cells INNATE T-lymphocytes with αβ TCR recognize MHC – peptide complexes expressed on the surface of professional antigen presenting cells (APC) T-cell recognition requires the physical contact of APC and T cell MHC RESTRICTION OF T-CELL RECOGNITION TCR TCR M HC MHC MHC APC APC APC TCR A given TCR recognizes a defined MHC – peptide complex The same peptide presented by another MHC is not recognized by the same TCR Another peptide bound to the same MHC is not recognized by the same TCR GENERATION OF MHC CONGENIC MICE P Mouse Y Mouse X F1 F2 20 times Mouse X (Y) Assembly of TCR and BCR APC MHC Antigen Antigen Antigen Antigen TCR BCR αβ s V s s sV s C s s sC ss P P D/E X7 D/E X2 YXXL/I X7 YXXL/I ITAM Immunoreceptor Tyrosine-based Activation Motif AKTIVÁCIÓ CD3 CD3 εδ s s s s εγ s s s s ζζ s s