1. ANTIGEN PRESENTING CELLS

2. Professional antigen presenting cells Definition: Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells. Critical for initiation of responses. Functions: Gatekeeper function: sensing pathogens, initiation of the T-cell response.  Antigen uptake and delivery to the site of antigen presentation. This way antigens are concentrated in the peripheral lymphoid organs, at the exact area where naive lymphocytes pass throuh while recirculating.  Provide second and third co-stimulation signals (CD80, CD86 …). Maintenance of self tolerance.

3. Comparison of APCs

4. Functions of different antigen-presenting cells

5. Capture and display of microbial antigens

6. DENDRITIC CELLS THE MOST EFFICIENT ANTIGEN PRESENTING CELLS

7. Development of dendritic cell subsets Stem cell monocyte blood tissue lymph node differentiation maturation Adaptive immunity bacteria virus phagocytosis interstitial

8. Dendritic cells use several pathways to process and present protein antigens Receptor-mediated endocytosis and macropinocytosis brings pathogens or pathogen derived antigens into the vesicular system ----- MHCII presentation. Receptor-mediated endocytosis and macropinocytosis brings pathogens or pathogen derived antigens into the vesicular system ----- MHCII presentation. Viral infection of dendritic cells directly allows presentation of viral proteins on Class I MHC. Viral infection of dendritic cells directly allows presentation of viral proteins on Class I MHC. Presentation of exogenous viral proteins on MHCI to CD8+ T-cells occurs via CROSS- presentation. Presentation of exogenous viral proteins on MHCI to CD8+ T-cells occurs via CROSS- presentation. Infected DCs release viral proteins and particles in the lymph node and infect resident DCs ---- - regular and CROSS-presentation. Infected DCs release viral proteins and particles in the lymph node and infect resident DCs ---- - regular and CROSS-presentation.

9. Dendritic cells take up antigens at a site of wounding and infection in the skin and carry them to the draining lymph node for presentation to naive T cells

10. Increased expression of: MHCII co-stimulatory molecules pro-inflammatory cytokines Dendritic cells as „gatekeepers” and APCs Changes in morphology and function in reponse to maturation signals

11. Dendritic cells as „gatekeepers” and APCs Changes in morphology and function in reponse to maturation signals MHCII Lysosomes LysosomesColocalization

12. Cell-surface molecules of the immunoglobulin superfamily initiate lymphocyte adhesion to professional antigen presenting cells Initial contactA. Transient interactions are stabilized by Ag- binding B. DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)

13. APCs deliver both positive and negative second/third signals to T-cells The B7 and CD28 families of co-receptors

14. Huang et al Immunity 2004 Bone-marrow derived DCs (yellow) were pulsed with 1 µM Ova 4 peptide and 10 µM Ova for 1 hour at 37 o C, then injected into the footpad of a C57BL/6 recipient. This was followed 6 hours later by i.v. co- injection of OT-I CD8+ T cells (5 µM CFSE, green) and OT-II CD4+ T cells (5 µM SNARF, red). Rapid DC migration in the subcapsular space Capture of antigen-specific T cells by antigen-bearing DCs Bone-marrow derived DCs (either 5 µM CFSE, green) or (50 µM Cell Tracker Blue, blue) were injected into the footpad of a C57BL/6 mouse, followed 18 hours later by intravenous injection of freshly isolated polyclonal CD4+ T cells (5 µM SNARF, red) and CD8+ T cells (5 µM CFSE and 5 µM SNARF, yellow). The draining LN was removed 6 hours after injection.

15. Interdigitating reticular (mature dendritic) cells in T cell areas of lymph nodes NUCLEUS CYTOPLASM T CELL

16. PLASMACYTOID DENDRITIC CELLS ARE TRUE ANTIGEN PRESENTING CELLS

17. Morphology of plasmacytoid dendritic cells IPC/DC2 monocytepDC Scanning EM Transmission EM PDC morphology is similar to plasma cells and monocytes. Electron microscopy reveals abundant RER. In human TLR9 is only expressed in pDCs.

18. Migration pathways of pDC/IPC versus mDC into a lymph node IPC: HEV mDC: afferent lymphatics Both migrate into the T-cell rich areas. Different path, same destination

19. Plasmacytoid DCs control the function of many immunocytes Role in immune response and in the pathogenesis of autoimmune diseases and cancer. IFNα is important in SLE pathology. Plasmacytoid DCs efficiently cross-present exogenous antigens to CD8+ T-cells when activated via TLR (Blood. 2008;112:3713-3722).

20. Bekeredjian-Ding, 23 May 2014 doi: 10.3389/fimmu.2014.00238 EFFECTOR FUNCTIONS OF pDCs

21. IMMUNOTHERAPY

22. Conventional dendritic cells as tools for immunotherapy The way DCs are activted will determine their functional activity. This is utilized to in vitro generate DCs for the treatment of various diseases.

23. A broad range of strategies are suitable to induce effective anti-tumor response being used to produce DCs in vitro Dendritic cell vaccines for tumor therapy Karolina Palucka and Jacques Banchereau, Nat Rev. Cancer 2012, p. 265

24. Receptor/ligand pairs of co-receptors expressed at the T-cell/APC interface Potential targets for immune modulation. Room for combinational therapy. NOT only for cancer!!!

25. PD1 delivers negative signals in T-cells via binding of the SHP-2 phosphatase to its ITSM motif Inhibiting PD-1 / PD- L1 interaction is a powerful tool for boosting anti-tumor responses. Very promising in PD-L1 positive melanomas! David F. McDermott etal Clinical therapeutics p. 764 2015.

26. Anti-PD-1 and PD-L1 blockade agents currently in clinical trials

27. Co-stimulatory blocade using a CTLA4-Ig construct

28. THE END