ANTIGEN-SPECIFIC T – CELL ACTIVATION MHC – peptide complex (ligand) PARTNERS Antigen presenting cell carrying antigenic peptides bound to MHC – pre-formed MHC – peptide complexes – INDEPENDENT ON T CELLS Self MHC with captured antigenic peptide interacts with antigen-specific T lymphocytes selected from the available T cell repertoire INTERACTION MHC – peptide complex (ligand) T cell receptor

MHC RESTRICTION One single T-cell receptor can recognize a given MHC – peptid complex If the peptide binds to another MHC molecule no T-cell recognition occurs If the same MHC molecule binds another peptide, no T-cell recognition occurs

RECOGNITION OF CORRECT MHC – PEPTIDE COMPLEXES BY THE SPECIFIC T-CELL Infected cell Normal cell T APC AND T CELL INTERACTION IS IT SUFFICIENT FOR T CELL ACTIVATION? WHERE AND WHEN CAN OCCUR? HOW IS IT INDUCED?

VARIABILITY AND ORIENTATION OF CDR IN THE T CELL RECEPTOR -chain -CHAIN Diszulfid hidak CDR1 CDR2 CDR3 -chain V C CDR1 and CDR2 are not hypervariable NO SOMATIC HYPERMUTATION Variability of CDR3 is the result of joining variability CDR1 CDR2 CDR3

INTERACTION OF THE T - CELL ANTIGEN RECEPTOR WITH AN MHC – PEPTIDE COMPLEX TCR - MHC1 TCR - MHC1 CDR3 - peptide The TCR is monovalent, binds a single MHC – peptide complex The affinity of the TCR – peptide – MHC interaction is low 10-5 - 10-6 M/l A defined MHC – antigenic peptide complex is displayed in the cell membrane together with various other MHC – peptide complexes (DILUTED LIGAND) How many MHC – peptide complexes are needed for T cell signaling?

THE IMMUNOLOGICAL SYNAPSE

THE IMMUNOLOGICAL SYNAPSE ANTIGEN PRESENTING CELL ICAM-1 LFA-1 B7 CD28 CD48 CD4 T CELL CD2 SIGNALING COMPLEX adaptor ICAM – Intercellular Adhesion Molecule ACTIVATED T CELL

APC T cell

THE INTERACTION OF T CELLS AND ANTIGEN PRESENTING CELLS recognition 1 2 3 4 5 6 7 8 stabilization separation Negulescu P.A. et. al. Immunity 4: 421-430, 1996

THE CONTACT OF APC AND T CELLS IS STABILIZED BY ADHESION MOLECULES MHCI – CD8 MHCII – CD4 CD40 – CD40L B7 – CD28 * B CELL T CELL

KINETICS OF LYMPHOCYTE ACTIVATION ANTIGEN SIGNAL1. Nyugvó limfocita G0 sejtosztódás DNA synthesis Effector cell Memory cell Transport Membrane change RNA and protein synthesis Resting lymphocyte G0 co-receptor Adhesion molecule Cytokines SIGNAL2. Resting lymphocyte G0 PTK activation RNA synthesis Free Ca++ Protein synthesis Protein phosphorylation DNA synthesis Lymphoblast 0 10sec 1min 5min 1hr 6 hrs 12 hrs 24 hrs

Similar but not identical signaling elements in B and T cells BCR TCR Lyn Kinases Syk Btk fyn ZAP70 Itk SLP-65/BLNK PLCg2 Adaptors + substrates PLCg1 SLP-76

T CELL RECEPTOR MEDIATED SIGNALING Multisubunit Immune Recognition Receptors MIRR α β ε δ ε γ ζ ζ ITAM Immunoreceptor Tyrosine-based Activation Motif ACTIVATION

TCR signaling Fyn

Role of transcription factors in T-sejt activation

A T-sejt aktiválás intracelluláris folyamatai INTRACELLULAR EVENTS OF T CELL ACTIVATION A T-sejt aktiválás intracelluláris folyamatai SIGNAL TRANSDUCTION Enzimatic modification (kinases, phosphatases, proteases) Local concentration (recruitment or sequestration of interacting components Timing (pathway can go to diverse directions, first one will be realized) Allosteric effects (binding activates or inactivates) NEW GENES

INVOLVEMENT OF ADHESION AND CO-STIMULATORY MOLECULES INTERACTION OF THE TCR WITH MHC-PEPTIDE COMPLEXES IS ESSENTIAL BUT NOT SUFFICIENT FOR T-CELL PRIMING INVOLVEMENT OF ADHESION AND CO-STIMULATORY MOLECULES CONVERGING SIGNALING PATHWAYS IN T CELL ACTIVATION CD4/CD8 costimulation CD28 costimulation

THE ADHESION AND CO-STIMULATORY MOLECULES CD4 AND CD8 MARKERS OF T CELL SUBPOPULATIONS ADHESION MOLECULE BINDS TO MHC SIGNALING MOLECULE TARGET CELL 1 3 2 2m 2 1 2 1 PROFESSIONAL APC CD8 Cytotoxic T-cell α β Helper T-cell CD4 SIGNAL

THE RATIO OF CD4+/CD8+ T CELLS IS STABLE IN HEALTHY INDIVIDUALS Normal CD4+ T-cell counts = 600 – 1400/ l HIV infection  AIDS = CD4+ T cell count <200/l