1. 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?

3. 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

5. 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

9. 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)

10. 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

11. 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- 1361 21 5.8x10 6 ~2x10 11 10 18 NO

12. 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?

13. 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

14. 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

15. © 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

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

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

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