Cell mediated immune response

1. Immune Response II Dr. sufi h. z. Rahman Mbbs , md (immunology) Lecturer, medical faculty, aucms

2. Objectives Role of antigen presenting cells in cellular immune response Role of lymphocytes in cellular immune response Mechanisms involved in cellular immune response Types cytokines and their role in cellular immune response Interaction between the components of the immune system in regulating immune response

3. Cell Mediated Immunity Provided by T lymphocytes Provides immunity to ( i ) intracellular bacteria (ii) viruses, (iii) fungi, (iv) protozoa and (v) tumours T cells can recognize antigen only when it is presented on the surface of Antigen presenting cells (APCs) by self MHC molecules This self MHC restriction results from positive selection during maturation of T cells in the thymus

4. Antigen Presenting Cells Cells that present antigens to T lymphocytes and activate them Express both Class I and Class II MHC molecules on surface Also express B7 (B7.1 and B7.2) molecules Present antigens by Class I MHC molecules to CD8+ T cells and by Class II MHC molecules to CD4+ T cells Professional APCs are Dendritic cells, Macrophages and B cells

5. Antigen Presenting Cells

6. Antigen Presentation APCs process and present antigens in two pathways Exogenous or Endocytic pathway: Phagocytosed microorganisms are degraded in the phagosomes and peptides are presented in this pathway by Classs II MHC molecules Endogenous or Cytosolic pathway: Intracellular microorganisms synthesize protein in the cytoplasm that are presented in this pathway by Class I MHC molecules

7. Antigen Presentation

8. Derived from bone marrow by haematopoiesis Progenitor T (Pro- T) cells migrate to thymus Maturation occurs in the thymus Rearrange TCR gene segments and acquire TCR Undergo two selection process Positive selection: Self MHC restriction Negative selection: Self tolerance Acquire surface CD molecules e.g. CD3, CD4/ CD8 Two population of T cells are released to the circulation: CD4+ or helper T (T H ) cells CD8+ or Cytotoxic T (T C ) cells T lymphocytes Maturation

9. Maturation of T lymphocytes in the Thymus e

10. T lymphocytes Maturation

11. Mechanism of CMI APCs present antigens by Class I MHC molecules to CD8+ (T C ) cells and by Class II MHC molecules to CD4+ T (T H ) cells T C B7 CD28 Antigen recognition by T cells

12. T cells recognize specific antigens presented with MHC molecules on the surface of APCs by TCR Each T cell has 10 5 TCRs on its surface all of which recognize a one antigen (or epitope) 10 10 clones of T cells will recognize 10 10 antigens Antigen recognition by T cells Mechanism of CMI

13. Antigen recognition by TCR provides Stimulatory signal (Signal 1) to the T cell Binding of B7 molecule on APC with CD28 molecule on T cell provides Co-stimulatory signal (Signal 2) to the T cell Antigen recognition by T cells Mechanism of CMI

14. When T cells receive both Stimulatory (Signal 1) and Co-stimulatory (Signal 2) signals they are activated (clonal activation) If the T cells receive only the Stimulatory signal without Co-stimulatory signal, they are permanently inactivated (clonal anergy ) Stimulatory signal+ Costimulatory signal= Activation Stimulatory signal without Costimulatory signal= Anergy T cell T cell T cell activation Mechanism of CMI

15. Activated T cells start to proliferate, synthesize and secrete IL-2 and express IL-2 receptors on cell surface After several divisions they differentiate to effector and memory T cell populations Memory T cells have long life span (20- 30 years) and provide immunity if the person is re-exposed to the same antigen T cell differentiation Mechanism of CMI

16. Effector T cells are short-lived (few days to weeks) cells and carry out specialized functions e.g. CD8+ effector T cells: Induce apoptosis of virus infected and tumour cells (Cytotoxic killing) CD4+ effector T cells: Secrete cytokines that cause macrophage activation to kill intracellular pathogens and to help T C cell and B cell activation T cells differentiation Mechanism of CMI

17. Antigen Elimination by CMI Cytotoxic T cells induce apoptosis of infected cells bearing antigen on the surface CD8+ Effector T cells

18. Antigen Elimination by CMI With influence of cytokines e.g. IL- 12 from APCs, T H cells differentiate to T H 1 cells T H 1 cells release cytokines e.g. interferon- g (IFN- g ) IFN- g activates macrophages that phagocytose and eliminate intracellular pathogens CD4+ Effector T cells

19. Antigen Elimination by CMI Activated macrophages have more phagocytic and killing activity and they phagocytose and kill intracellular pathogens effectively CD4+ Effector T cells

20. Naïve cytotoxic T cells (cytotoxic T cell precursor) require cytokines from T H cells for activation T H cells help T C cell activation Regulatory role of T H cells

21. Activation of naïve B cells require Direct interaction with T H cells by Antigen in Class II MHC and TCR CD40 and CD40L B7 and CD28 Cytokines from T H cells T H cells help B cells T H cells help B cells to induce humoral immune response Regulatory role of T H cells

22. Regulatory Role of T H cells Cytokines from T H 1 cells also help T C cell activation Thus T H 1 cells regulate CMI With the influence of IL-4 (from mast cells?) T H cells differentiate to T H 2 cells Cytokines from T H 2 cells help B cell activation Thus T H 2 cells regulate humoral immunity

23. 4a. Activated T cells differentiate to effector T cells and memory T cells (macrophages) Interaction between the components of the immune system CD4+ T (T H ) cells regulate the function of both T C and B cells

24. T H cell activation by Superantigens Superantigens are viral or bacterial proteins that bind simultaneously to the V b domain of a TCR and to the a chain of class II MHC molecule They bind outside of the TCR antigen binding cleft Any T cell expressing a particular V b sequence will be activated by a corresponding superantigen

25. Hence, the activation of T H cells by superantigens is polyclonal and can affect a huge number T H cells It results in overproduction of cytokines from T H cells (e.g. IL-2) and from macrophages (e.g. IL-1, TNF) Huge amount of cytokines produce toxic systemic effects e.g. shock, vomiting, diarrhoea, organ failure etc. rather than providing immunity Super antigens are usually soluble proteins secreted by bacteria (exogenous) but may be membrane bound proteins of some viruses (endogenous) T H cell activation by Superantigens

26. Superantigen Disease Enterotoxin of Staphylococcus aureus Food poisoning Toxic shock syndrome toxin (TSS1) of Staphylococcus aureus Toxic shock syndrome Exfoliative dermatitis toxin of Staphylococcus aureus Scalded skin syndrome Erythrogenic toxin of Streptococcus pyogenes Scarlet fever Pyrogenic toxin of Streptococcus pyogenes Streptococcal Toxic shock syndrome Mycoplasma arthritidis supernatant Arthritis, Shock T H cell activation by Superantigens

27. Cytokines Protein molecules secreted by cells that regulate function of that cell or other cells The name denotes their role in cell to cell communication Development of an effective immune response involves lymphocytes and other leukocytes Cytokines play key role in the complex interaction between cells of the Immune system

28. Cytokines Autocrine : Acts on the same cell that secretes it Paracrine : Acts on adjacent cells Endocrine: Carried by the blood or body fluid to a distant site and acts on distant cells

29. Cytokines One cytokine may act on various cells and produce various effects Many cytokines may act on the same cell and produce same effect One cytokine may increase action of the other One cytokine may inhibit action of the others

30. Cytokines Cytokines secreted by some leukocytes and acting on other leukocytes are called interleukins Cytokine secreted by lymphocytes are called lymphokines Cytokines secreted by monocytes and macrophages are sometimes called monokines Cytokines that cause chemotaxis of leukocytes are called chemokines

31. Cytokines

32. Further Review Levinson W. Review of Medical Microbiology and Immunology . 11 th edition. McGraw Hill, 2008. Kindt TJ, Goldsby RA, Osborne BA. Kuby Immunology . 6 th ed. WH Freeman, 2006. Abbas AK, Lichman AH. Basic Immunology . 3 rd edition. Elsevier, 2011.