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

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

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

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

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

ESTIMATED VARIABILITY OF IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES GÉNEK/ KAPCSOLÓDÁS IMMUNOGLOBULIN H  /  VARIABLE (V) 65 70 DIVERZITY (D) 27 D (3 frame) rare - JOINING (J) 6 5/4 JOINING + P + N 2 1 V GENE PAIRS 3.4x106 JOINING ~3x107 TOTAL ~1014 T CELL RECEPTOR   52 ~70 2 OFTEN - 13 61 1 5.8x106 ~2x1011 1018 NO SOMATIC HYPERMUTATON

T – CELLS PROMOTE B – CELL DIFFERENTIATION ANTIGEN CYTOKINES 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 The TCR is not able to interact directly with soluble or cell-bound antigen T-cell activation can be induced by antigen in the presence of acessory cells, only 3. T-cells recognize virus-infected cells ACCESSORY CELL NO INTERACTION ANTIGEN BINDING T-CELL ACTIVATION T-CELL Antigen receptor B-CELL

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

THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976 Virus B + Y cells T Virus A T - CELLS T Specific for self and virus MOUSE Y Virus A + Y cells T MOUSE X Virus A + X cells T Virus A + X cells T The virus infected cell must derive from the same organism as the T cell © M e d i a G r a p h i c s I n t e r n a t i o n a l

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

Mouse Y and the congenic Mouse X(Y) carry an identical MHC gene locus 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 immune response to protein antigens is also dependent on MHC genes THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX AND THE RESPONE TO PROTEIN ANTIGENS Antigen Antigen Mouse Y Mouse X NO IMMUNE RESPONSE 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

TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES 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 T-LYMPHOCYTES RECOGNIZE ANTIGEN-DERIVED PROTEIN FRAGMENTS (PEPTIDES) EXPRESSED ON THE SURFACE OF SELF ANTIGEN PRESENTING CELLS

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

Y ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES T Y Cell surface MHC-peptide complex T-cell response soluble Ag Peptide antigen Native membrane Ag Cell surface peptides APC No 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 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 X Mouse Y F1 F2 20 times Mouse X (Y)

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