PLASMA CELL ANTIGEN CYTOKINES B -CELL T – CELLS PROMOTE B – CELL DIFFERENTIATION ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY WHAT IS THE STRUCTURE OF THE T – CELL RECEPTOR?

C mIg H mIg L TCR  TCR  T-SEJT  C V Antigen receptor TCR B and T cell receptors are similar 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 Single binding site No somatic mutation

Chr 7 Chr 14  -chain locus  and δ-chain locus  -chain locus  -gene rearrangement results in the elimination of the δ gene Sequence of D genes allows reading in 3 reading frames No strict 12 – 23 rule for δ-genes (DJ and VD recombination) Chr 7 TCR1 =  TCR2 =  δ LOCATION OF TCR GENES L1 V  1 Ln V  n D  1 J  1 C  1 D  2 J  2 C  2  -enhancer L1 V  1 Ln V  n J  1 C  1 J  2 C  2  -silencer, enhancer L1 Vδ1 L2 Vδ2 L3 Vδ3 Dδ1Dδ2Dδ3Jδ1Jδ2Jδ3 Cδ L4 Vδ4 L1 V  1 Ln V  n J  1-n C  1

T-CELL Antigen receptor TCR V C  The VARIABLE REGIONS OF  - AND  -CHAINS ARE GENERATED BY SOMATIC RECOMBINATION mRNS not functional Recombination of V  and J  genes can occur after multiple unsuccessful recombination next funcional further functional (no allele exclusion)

CDR1 CDR2 CDR3  -chain  -chain CDR1 CDR2 CDR3 VCVC  -CHAIN Diszulfid hidak CDR1 and CDR2 loops are not hypervariable NO SOMATIC HYPERMUTATION Variability of CDR3 is the result of joining variability

GÉNEK/ KAPCSOLÓDÁS IMMUNOGLOBULIN H  / VARIABLE (V) 6570 DIVERZITY (D) 270 D (3 frame) rare- JOINING (J) 65/4 JOINING + P + N 21 V GENE PAIRS 3.4x10 6 JOINING ~3x10 7 TOTAL ~10 14 SOMATIC HYPERMUTATON ESTIMATED VARIABILITY OF IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES T CELL RECEPTOR  52~70 20 OFTEN x10 6 ~2x NO

PLASMA CELL ANTIGEN CYTOKINES B -CELL T – CELLS PROMOTE B – CELL DIFFERENTIATION ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY HOW T – CELLS RECOGNIZE ANTIGENS?

ANTIGEN BINDING NO INTERACTION ACCESSORY CELL T-CELL ACTIVATION Antigen receptor T-CELL B-CELL 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

T-LYMPHOCYTES RECOGNIZE VIRUS-INFECTED CELLS Virus-infected cell Cytotoxic T-lymphocytes kill virus-infected cells virus Killed virus-infected cellInfected cell Citotoxic T-cell T-cells do not interact with virus particles

© Media Graphics International MOUSE Y Virus A T - CELLS T T T T T T Virus B Virus B + Y cells T Virus A + Y cells T MOUSE X Virus A + X cells T Virus A + X cells T T THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976 The virus infected cell must derive from the same organism as the T cell Specific for self and virus

THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX MHC Mouse X Thymus removal (No T cells) Mouse Y Mouse X ORGAN REJECTION IS MEDIATED BY T-CELLS

Mouse X (Y) Mouse 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 CONGENIC MICE SHARE COMMON MHC GENES 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 HISTOCOMPATIBILITY IS DETERMINED BY GENES OF THE MHC

Mouse X Mouse Y 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 THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX AND THE RESPONE TO PROTEIN ANTIGENS Antigen IMMUNE RESPONSE NO IMMUNE RESPONSE Antigen

T-LYMPHOCYTES RECOGNIZE ANTIGEN-DERIVED PROTEIN FRAGMENTS (PEPTIDES) EXPRESSED ON THE SURFACE OF SELF ANTIGEN PRESENTING CELLS VIRUS-INFECTED CELLS ARE RECOGNIZED BY T- LYMPHOCYTES IN MHC-DEPENDENT MANNER TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES THE IMMUNE RESPONSE TO PROTEIN ANTIGENS IS REGULATED BY INDIVIDUALLY POLYMORPHIC MHC GENES

ANTIGEN PRESENTING CELLS endogenous antigens Synthesize antigens – endogenous antigens (virus, tumor) exogenous antigens Internalize antigens – exogenous antigens (any protein) processing Degrade protein antigens to peptides – processing antigen presentation 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 Y T No T-cell response soluble Ag Native membrane Ag Peptide antigen Cell surface MHC- peptide complex T-cell response Cell surface peptides APC

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 APC) 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 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

α βα β ε δ ε γ ζ ζζ ζ ITAM Immunoreceptor Tyrosine-based Activation Motif AKTIVÁCIÓ Assembly of TCR and BCR Antigen

F1 P Mouse X Mouse Y F2 GENERATION OF MHC CONGENIC MICE 20 times Mouse X (Y)