ANTIGEN-SPECIFIC T – CELL ACTIVATION PARTNERS

1. ANTIGEN-SPECIFIC T – CELL ACTIVATION PARTNERS Antigen presenting cell carrying antigenic peptides bound to MHC – pre-formed MHC – peptide complexes 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

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

3. 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

4. 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?

5. THE IMMUNOLOGICAL SYNAPSE

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

7. APC T cell

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

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

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

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

12. T CELL RECEPTOR MEDIATED SIGNALING εδεγ αβ ζζ Multisubunit Immune Recognition Receptors MIRR ITAM Immunoreceptor Tyrosine-based Activation Motif ACTIVATION

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

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

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

16. THE RATIO OF CD4+/CD8+ T CELLS IS STABLE IN HEALTHY INDIVIDUALS CD4+ : CD8+ = 1.6 Normal CD4+ T-cell counts = 600 – 1400/ l HIV infection  AIDS = CD4+ T cell count <200/l