Specific Defenses of the Host

1. Specific Defenses of the Host The Immune response

2. The Immune System

3. Acquired (specific) immunity • The Acquired immune system recognizes foreign substances and develops a specific immune response against them. • Substances that provoke an immune response are calledAntigens(Ag). • Bacteria, viruses, fungi, protozoa, helminthes, and cancerous cells are examples. • The main type of cells of the Acquired immune system are lymphocytes.

4. Humoral immunity B-cells (B- lymphocytes) Carried out by Antibodies Effective against Extracellular antigens (antigens outside our cells like bacteria) MHC independant Cell mediated T-cells (T-lymphocytes) Carried out by Perforin Effective against Intracellular antigens (antigens inside cells i.e.… viruses) Cancer Tissue transplant rejection. MHC dependant Acquired (specific) immunity

5. Cell Mediated Response T cytotoxic (Tc ) cells

6. T- cells • Thymocyte (immature T-cells) are produced by the bone marrow. • Thymocytes are immature and are unable to react with antigen • They travel to the thymus where they are screened and mature into T-cells. • Mature T cells must be able to distinguish between self and non-self.

7. Distinguishing self from non-self

8. Question • How do T-cells recognize self cells (The cells that make up your body) from foreign cells? • Answer: They bind to and analyze a protein marker found on all of your cells called the Major Histocompatability complex (MHC).

9. Major Histocompatability complex(MHC) The MHC is a marker found on all of your cells. • It identifies your cells as “self” to your immune system. • The MHC also randomly picks up proteins from inside your cell and displays them on the outside to your immune system • T-cells must be able to differentiate your MHC markers from others

10. Positive selection of Thymocytes in the thymus. • Thymocytes that enter the thymus are self programed to die. • The thymoctyes that are able to recognize the MHC and bind to it receive a signal that allows them to live. • All thymocytes that are unable to bind to your MHC die.

11. Question • How do your T-cells recognize unhealthy body cells harboring intercellular parasites from your normal healthy cells?

12. Answer: • The bone marrow generates T- cells that collectively are able to recognize any possible protein in the context of your MHCs. • The T-cells that bind to healthy normal self-proteins in the context of an MHC die in the thymus. • Only T-cells that are able to bind to an MHC coupled with a foreign protein are released out to the body. • This is called Negative selection

13. The MHC constantly samples proteins in the cytoplasm. • The MHC displays these proteins to the immune system outside the cell. • If the protein displayed is normal and are regularly found in the cell, the T-cells will not attack. • If the protein in the MHC is foreign, (ie…viral protein) the T-cells will attack the cell.

14. Screening of T-cells • In the thymus, Thymocytes undergo a double screening process. • Positive selection: Selects for thymoctes that have receptors capable of binding self-MHC. These cells are given a positive stimulus which allow them to live. • Thymocytes that fail positive selection die. • Negative selection: selects against thymocytes that are able to bind self proteins presented by self-MHC. • Thymocytes that have high affinity receptors for self proteins receive a negative stimulus that causes them to die.

15. Results of Positve and Negative Screening • The T-cell repertoire in the body consists of T-cells which are only able to recognize foreign proteins in the context of self MHC. • The Cell mediated response is MHC restricted

16. Turning on the Specific Immune Response A job left to the Innate Immune system

17. Overview of Cell Mediated Response • Antigen presenting cells (APC) ingest microbes and present the Antigens to a type of T-cell called a T-Helper cell (TH-cell). • The TH-cell becomes activated and secretes a cytokine called interleukin 2. • Interleukin 2 from the TH-cell, binds to T Tc-cell and has 2 effects. • 1. Activates Tc-cells causing them to produce perforin molecules. These cells are now able to kill infected host cells. • 2. Causes activated Tc-cells to proliferated and go through clonal expansion.

18. The non-specific or innate immune response turns on the specific immune response. • APC (macrophages, dendritic cells and B cells) ingests a microbe. • The microbe is processed into short antigenic fragments • These fragments are combined with a MHC molecule inside the APC. • The MHC /Ag complex is presented on the surface of the APC MHC II /AG complex Antigen Presenting Cell (APC)

19. T Helper cells • The APC travels to the lymph node where it meets T-helper cells (TH-cells) • A TH-cell with an appropriate receptor binds to the MHC II /Ag complex. • This is called the primary signal • The Primary signal causes receptors for interleukin 2 to be expressed on the surface of the TH-cell. V V V Interleukin 2 receptors (IL-2)

20. Co-stimulatory signal • B7 protein on the APC binds to a CD28 receptor on the TH-cell. • This is called the Costimulatory signal • The costimulatroy signal induces the TH-cell to produce and secrete IL-2.

21. Interleukin 2 • The costimulatroy signal induces the TH-cell to produce and secrete IL-2. • The IL-2 binds to IL-2 receptors on the TH-cell.

22. Clonal Expansion • IL-2 causes the TH-cell to clone itself over and over. • The TH-cell is now ready to activate a T-cytotoxic cell.

23. Activating Tc-cells • T cytotoxic cells (Tc-cells) migrate into an area of infection by chemotaxis. • A Tc-cell with an appropriate T-cell receptor binds to an MHC I /Ag complex. • This binding stimulates the Tc-cell to produce receptors for IL-2 Infected Cell MHC I /Ag TCR C IL-2R

24. Differentiation of Tc-cells • After the IL-2Rs are expressed on the outside of the Tc-cell the Tc-cell lets go of the infected body cell and migrates into lymph-nodes or other lymphatic tissues. • If the Tc-cells in the lymphatic tissue finds an activated TH-cell and receives IL-2 it will proliferate into active T cytotoxic lymphocytes and memory cells.

25. Cell Mediated Cytolysis

26. IL-2

27. The MHC Question • Why doesn’t activated Tc-cells bind to the APCs and kill them?

28. Answer to MHC Problem • There are two different types or classes of MHCs: MHC I and MHC II

29. MHC I. • This class is found on every nucleated cell of the body. • Proteins and antigens bound to MHC I are always taken up from the pool of free floating proteins in the cytoplasm. • Only T-cytotoxic cells are able to bind to this class of MHC. • Tc cells can only kill cells with MHC I.

30. MHC II • This class is only found on the surface of APCs. • Antigens that are bound to this class of MHC are always taken from phagolysomes. • This means that the cell is healthy • Only T-Helper cells can bind to this class of MHC • TH-cells activate Tc- cells but never kill cells that they interact with. Thus APCs are perserved.