The Adaptive Immune Response

1. The Adaptive Immune Response Jeffrey Tso Karen Ka Yan Ng Kaitai Ye Marina Simeonova PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

3. Time course of the Adaptive Immune Response Janeway’sImmunobiology, 2012

4. Antigen Processing, Prep and Presentation Janeway’sImmunobiology, 2012

5. Dendritic Cell Path

6. Stimulation of T cells by Dendritic Cells Janeway’sImmunobiology, 2012

7. Stimulation of T cells by Dendritic Cells Janeway’sImmunobiology, 2012

8. T Cell Proliferation and Differentiation Janeway’sImmunobiology, 2012

9. Effector T cell Differentiation • Activated T cells become effector T cells, and differentiate to fill various roles. The role depends on the type of interleukins that the cells are exposed to. • Types of T cells include: Janeway’sImmunobiology, 2012

10. Cytotoxic T cells Janeway’sImmunobiology, 2012

11. T Helper Cells Janeway’sImmunobiology, 2012

12. T Helper Cells Janeway’sImmunobiology, 2012

13. T Regulatory Cells (Tregs) • Help regulate the immune response • Suppress activation of immune system when no infection present • Down-regulated in times of infection • Deficiencies in regulatory T cells can lead to autoimmune diseases

14. T Cell Independent B Cell Activation • Naïve B Cell recognize free (soluble) antigen using their BCR or membrane bound-immunoglobulin. • Rapid response, no isotype switching, no affinity maturation

15. T Cell Dependent Linked Recognition • For Thymus Dependent (TD) Antigens • Antigen-MHC Signal- B Cell Antigen MHC 2 – T Cell Receptor (TCR) • T Cell induced to express CD40 Ligand, CD30 Ligand- B Cell CD40, CD30 • T Cell secretes cytokines ie. IL4,5,6 and B Lymphocyte stimulator (BLyS) • Slower response, isotype switching, and affinity maturation Janeway’sImmunobiology, 2012

16. Janeway’sImmunobiology, 2012

17. Isotype Switching Janeway’sImmunobiology 2012

18. Isotype Switching • Antibodies as know as immunoglobulins are molecules ranging from 146-188kDa and 980kDa for IgM. • Important to form tailored antibodies to the infection • Vh, Vl, C domain • Naive B Cells express primarily IgM and IgD, but serum levels of IgM are less than 10%, with IgG being the most abundant • Th Cell CD40 Ligand, IL4, TFG-Beta, INFy- alternate splicing of Ig mRNA • Light chain variable for every pathogen depending on the presented antigen

19. Purpose of Antibodies • Opsonize Pathogens (IgGs) • Neutralize Toxins (IgG and IgA) • High affinity Ig’s may limit viral infectivity (IgA and IgG vs hemagglutininin influenza) • Activate complement

20. TYPES OF ACTIVATED B CELLS PLASMA B CELLS MEMORY B CELLS B-1 CELLS B-2 CELLS Marginal Zone B cells Regulatory B cells

21. Plasma B cells • Also known as Plasma cells, plasmocytes, effector B cells • Large B cells that have been exposed to antigen secrete large amounts of antibodies • Assists in the destruction of microbes  easier target for phagocyte + activation of complement system

22. Plasma B cells • Sometimes referred to as antibody factories • Large amounts of Rough ER (to synthesize the antibody) • Short lived, undergo apoptosis when the inciting agent that induced immune response is eliminated.

23. Memory B cells • Differentiate from activated B cells predominately from a germinal center. • Specific to the antigen encountered during the primary immune response • Able to live for very long time • Can respond quickly following a second exposure to the same antigen

24. B-1 Cells • Express IgM in greater quantities than IgG • Low in numbers in the lymph nodes and spleen and are instead found predominantly in the peritoneal and pleural cavity

25. B-2 Cells • Cells intended when using the unqualified “B cell” • Majority in the spleen and lymph • Cells are small, long lived resting cells that express low levels of surface IgM and high amounts of IgD • Unlike B-1 cells, these cells do not express CD4 antigen found on all T cells

26. Regulatory B Cells • B cells involved in immune regulation via various mechanism • Also known as Breg cells • Positive regulators of immune because of capability to produce antibodies, including antibodies • Production of antibodies facilitate optimal CD4+ T-cell • Also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact

27. 3 signals are needed in order for an Antigen Presenting Cells (APCs) to stimulate a naïve T cells: 1. Antigen Specific Signal: MHC Class II + TCR 2. Co-stimulatory Signal: B7 + CD28 3. Differentiation Signal: APC secretes a variety of cytokines promoting different effector T cell outcomes An absence of the antigen-specific signal will lead to anergic or clonally deleted T cells Types of Effector T-Cells Cytotoxic T cells (Tc/CD8): kills infected cells Helper T cells (Th/CD4): Th1, Th2, Th17- activates other immune cells ie. Naïve B Cells Treg:regulates immune response B Cells Naïve B cells are activated via T Cell independent or dependent route. Independent: pathogen phagocytosis using BCR, non-isotype switching antibody production Dependent:linked recognition: phagocytosis; display on MHC Class 2, interact with Th Cell which presents (CD40) Ligand and B Lymphoctyte stimulator (BLyS) Activated B Cells Plasma Cells: migrate to cite of infection and secrete antibodies Memory B Cells- assist in future response to the same antigen Regulatory B Cells- Secrete cytokines to regulate immune responses Antibody Isotype Switching 2 variable regions, light(VL) and heavy(VH) Primarily IgM, highest levels in serum IgG. Th Cell CD40L is necessary for Ig splicing and isotype switching to occur Antibodies can: opsonize pathogens, neutralize toxins, limit viral infectivity, activate complement pathway Summary slide

28. References • Janeway et al. (2001), Immunobiology: Garland Publishing, New York • Neuberger, M. S.; Honjo, T.; Alt, Frederick W. (2004). Molecular biology of B cells. Amsterdam: Elsevier. pp. 189–191. ISBN 0-12-053641-2. • Lang ML (Aug 2009). "How do natural killer T cells help B cells?". Expert Rev Vaccines 8 (8): 1109–21. doi:10.1586/erv.09.56. PMC 2747240.PMID 19627191. • Martin F, Kearney JF. Marginal-zone B cells. Nat Rev Immunol. 2002;2(5):323–335. • Neuberger, M. S.; Honjo, T.; Alt, Frederick W. (2004). Molecular biology of B cells. Amsterdam: Elsevier. pp. 189–191. ISBN 0-12-053641-2. • Lang ML (Aug 2009). "How do natural killer T cells help B cells?". Expert Rev Vaccines 8 (8): 1109–21. doi:10.1586/erv.09.56. PMC 2747240.PMID 19627191. • Martin F, Kearney JF. Marginal-zone B cells. Nat Rev Immunol. 2002;2(5):323–335.