1. 6th SEMINAR THE ADAPTIVE IMMUNE RESPONSE: ACTIVATION OF B AND T CELLS

2. SECONDARY LYMPHOID ORGANS/TISSUES Sites of lymphocyteactivation and terminaldifferentiation • LYMPH NODES • SPLEEN • TONSILS (Waldeyer’s ring) • Diffuse lymphoid layers under the epithelial barriers: • SALT (skin-associated lymphoid tissue) • MALT (mucosa-associated lymphoid tissue) • BALT (bronchus-associated lymphoid tissue) • GALT (gut-associated lymphoid tissue)

3. T AND B CELLS HAVE THEIR OWN AREAS IN THE SECONDARY LYMPHOID ORGANS

4. ACTIVATION OF LYMPHOCYTES IN LYMPH NODES

5. ACTIVATION OF DENDRITIC CELLS

6. T CELLS ENCOUNTER ANTIGEN-LOADED APCsIN THE SECONDARY LYMPHOID ORGANS

7. ACTIVATION OF T CELLS APC T

8. THE IMMUNOLOGICAL SYNAPSE • Outer ring: • cell adhesion molecules • Inner ring: • TCR – peptide – MHC complex • coreceptor • costimulatory molecules • cell adhesion molecules

9. MULTIPLE STEP MODEL OF T CELL ACTIVATION INTERACTION OF THE TCR WITH MHC-PEPTIDE COMPLEXES IS ESSENTIAL BUT NOT SUFFICIENT FOR T-CELL PRIMING Involvement of adhesion and co-stimulatorymolecules Convergingsignalingpathwaysin T cellactivation CD4/CD8 coreceptor CD28 costimulation

10. T CELL CORECEPTORS

11. COSTIMULATION • Coreceptors (CD4/CD8) and costimulatory molecules of APCs (B7, CD40) grant extra activatory signals to antigen recognizing T cells • These extra signals are required to reach the threshold of activation • This is also a safety measure to avoid activation of autoreactive T cells, thus it is part of theperipheral tolerance mechanisms

12. ANTIGEN-RECOGNITION AND COSTIMULATION MUST OCCUR AT THE SAME TIME, THE SAME SITE, BY THE SAME APC

13. T CELL ACTIVATION AND SIGNALING CSA, tacrolymus rapamycin

14. EFFECTS OF T CELL ACTIVATION • Activation of transcription factors change the gene expression profile of the activated cell • Activated T cells start the transcription of the alpha chain of the IL-2 receptor and the IL-2 cytokine itself • The binding of IL-2 to the high affinity IL-2 receptors promotes proliferation (clonal expansion) of activated T cells • AfterproliferationT cellsdifferentiateintoeffectorormemorycells

15. DIFFERENTIATION OF CD4+ T CELLS • The polarization of helper T cell response is regulated by multiple factors: • origin of the presented peptide • nature of the APC • microenvironment • etc. • In case of an infection both Th1 and Th2 cells are generated in different sites of the secondary lymphoid organs • Imbalance occurs in case of special disorers: • Th1 dominance: e.g. mycobacterial infection • Th2 dominance: e.g. allergy, SLE cellular pro-inflammatory humoral anti-inflammatory

16. ACTIVATION OF CD8+ T CELLS

18. ACTIVATION OF B CELLS

19. MHCII T cell +peptide 1 B cell CD4 TCR 2 cytokines T CELL-DEPENDENT ACTIVATION OF B CELLS • Like naive T cells, naive B cells also require extra activatory signals for priming • B cells are APCs, they are able to take up soluble antigens, process them and present peptide derivates to helperT cells • T cells that recognize a peptide antigen presented by a B cell, produce cytokines with which they promote B cell activation and proliferation Polysacharides are not presented!

20. T CELL-INDEPENDENT ACTIVATION OF B CELLS TI-1 TI-2 B cell (extra activation signal) (extensivereceptor-aggregation) Simultaneous activation of BCR and other receptors on B cells (e.g. TLRs) induces the B cells to proliferate and differentiate Strong crosslinking of BCRsby repetitive polysaccharide or protein epitopes B CELL ACTIVATION

21. T CELL-INDEPENDENT ACTIVATION OF B CELLS

22. EFFECTS OF B CELL ACTIVATION • Proliferation (clonal expansion) • Differentiation to plasma cell and memory B cell • Antibody production • Affinity maturation • Isotype switch

23. MIGRATION OF B CELLS UPON ACTIVATION

24. THE GERMINAL CENTER REACTION • Proliferation (centroblasts) • T cell-mediated changes: • Somatic hypermutation(point mutations in the CDRs)  affinity maturation • Isotype switch (switch recombination)  adapted effector functions of ABs

26. PRIMARY AND SECONDARY (ADAPTIVE) IMMUNE RESPONSE

27. nonspecific • immediate reaction • does not improve • no memory • highly specific • develops in several days • improves after exposure • has memory