1. GENERAL IMMUNOLOGY PHT 324
Dr. Rasheeda Hamid Abdalla
Assistant Professor

2. Cell Mediated Immunity(CMI)

3. Objectives Cells of Cell Mediated Immunity MHC molecules
Mechanisms of Evading Cell-Mediated Immunity
Activating Macrophages and NK Cells

4. Cell Mediated Immunity (CMI)
An immune response that does not involve antibodies but rather involves:
Activation of macrophages and NK-cells.
Production of antigen-specific cytotoxic T-lymphocytes.
Release of various cytokines in response to an antigen.

5. Cell Mediated Immunity (CMI)
Cell-mediated immunity is directed primarily against:
Antigens embedded in membranes of cells.
It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers and intracellular bacteria.
It also plays a major role in transplant rejection.

6. Cells of Cell Mediated Immunity

7. MHC molecules
Known as Human Leukocyte Antigens or HLA, are cluster of genes in the human DNA known as the Major Histocompatibility Complex (MHC).
They are present on various human cells and enable T-lymphocytes to recognize epitopes and discriminate self from non-self.

8. Unlike B-cell receptors on B-lymphocytes that are able to directly bind epitopes on antigens.
T-cell receptors of T-lymphocytes can only recognize Epitopes -typically short chains of amino acids called Peptides- after they are bound to MHC molecules.

9. MHC-I Molecules (Class I HLA)
MHC-I are made by all Nucleated cells in the body and possess a deep groove that can bind Peptide epitopes from endogenous antigens.

10. Endogenous antigens are proteins being produced within the human cell such as
viral proteins produced during viral replication,
proteins produced by intracellular bacteria such as Rickettsias and Chlamydia during their replication,
and tumor antigens produced by cancer cells.

11. MHC-II Molecules (Class II HLA)
MHC-II are made primarily by antigen-presenting cells or APCs.
APCs include
macrophages,
dendritic cells
B-lymphocytes.
MHC-II molecules have a deep groove that can bind Peptide epitopes from exogenous antigens.

12. Exogenous antigens are antigens that enter from outside the body such as bacteria, fungi, protozoa, and free viruses

13. T4-Lymphocytes (T4-Helper Cells, CD4+ Cells)
T-lymphocytes: refer to lymphocytes that are produced in the bone marrow but require interaction with the thymus for their maturation.
T4-lymphocytes are T-lymphocytes displaying a surface molecule called CD4.

14. They also have on their surface, epitope receptors called T-cell receptors (TCRs) that, in cooperation with the CD4 molecules, have a shape capable of recognizing peptides from exogenous antigens bound to MHC-II molecules on the surface of APCs and B-lymphocytes.

15. The TCR recognizes the peptide while the CD4 molecule recognizes the MHC-II molecule.
This represents the first signal necessary for activation of the T4-lymphocyte.

17. T8-lymphocytes (T8-Cells; CD8+ Cells; Cytotoxic T-Lymphocytes)
T8-lymphocytes are T-lymphocytes displaying a surface molecule called CD8.
T8-lymphocytes also have on their surface, T-cell receptors (TCRs) similar to those on T4-lymphocytes, however, the TCR on T8-lymphocytes, in cooperation with CD8, bind peptides from endogenous antigens bound to MHC-I molecules.

18. The TCR recognizes the peptide while the CD8 molecule recognizes the MHC-I molecule

19. Natural killer cells (NK cells)
NK cells are another group of cytolytic lymphocytes, distinct from B-lymphocytes and T-lymphocytes.
They participate in both innate immunity and adaptive immunity.
NK cells are lymphocytes that lack B-cell receptors and T-cell receptors.
They are designed to kill certain mutant cells and virus-infected cells.

20. The Lymphoid System
The body uses the lymphoid system to enable lymphocytes to encounter antigens and it is here that adaptive immune responses are initiated.
The lymphoid system consists of
primary lymphoid organs
secondary lymphoid organs
and lymphatic vessels.

22. Ways that Cell-Mediated Immunity Defend the Body

23. Activating antigen-specific cytotoxic T-lymphocytes (CTLs)
Cytotoxic T-lymphocytes (CTLs) produced during cell-mediated immunity are designed to remove body cells displaying "foreign" epitope, such as
- virus-infected cells,
-cells containing intracellular bacteria
- and cancer cells with mutant surface proteins

24. The CTLs are able to kill these cells by inducing a programmed cell death known as Apoptosis.
CTLs induce apoptosis by 2 different pathways.

25. The first and most effective pathway involves intracellular granules.
The CTLs contain granules composed of proteoglycans.
These granules hold pore-forming proteins called Perforins and proteolytic enzymes called Granzymes.

27. When T cell Receptors (TCR) and CD8 of the CTL binds to the Major Histocompatibility Complex 1 (MHC-I)/epitope on the surface of the virus-infected cell, this sends a signal through CD3 molecule which triggers the release of Perforins and Granzymes

29. The Perforin molecules form pores in the membrane of the infected cell.
The pores increase permeability of infected cell and contribute to cell death.
The perforin pores also allow granzymes to enter.
Certain granzymes, in turn, can then activate the Caspase enzymes that lead to apoptosis of the infected cell.

31. 2. CTLs can also trigger apoptosis of the infected cells through FasL/Fas interactions.
- CTLs have a receptor called FasL that can also interact with Fas molecules found on the surface of most cell types.
This FasL/Fas interaction also triggers an intracellular transduction that leads to destruction of cytoskeletal structural proteins in the infected cell and chromosomal degradation

33. Death by apoptosis does not result in release of cellular contents such as inflammatory mediators.
Instead, the cell breaks into fragments that are subsequently removed by phagocytes.
Since CTLs are not destroyed in these reactions, they can function over and over again to destroy more virus-infected cells.

34. Mechanisms of Evading Cell-Mediated Immunity
1. Because of high rate of mutation, some viruses like HIV and hepatitis C virus (HCV) change the amino acid sequence and therefore the shape of key epitopes.
CTLs with TCRs made against the earlier strains of these viruses may no longer bind to and can not lyse cells infected with mutated strains of these viruses.

35. 2. Numerous viruses, such as Adenoviruses and some tumor cells can block the formation of MHC-I molecules by the infected cell.
As a result, CTLs are no longer able to recognize that if the cell is infected and cannot kill it.

36. Activating Macrophages and NK Cells
Cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) produced by Th1 lymphocytes activate macrophages, enabling them to destroy intracellular pathogens.

38. b. Activating NK Cells
Cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) produced by Th1 lymphocytes activate NK cells.
NK cells appear to use a Dual Receptor System in determining whether to kill or not kill human cells

39. The first receptor, called killer-activating receptor, can bind to a number of different molecules usually present on nucleated human cells, and this sends positive signal which enables NK cell to kill the cell to which it has bound unless the second receptor cancels that signal.
The second receptor, called killer-inhibitory receptor recognizes MHC-I molecules which are also usually present on all nucleated human cells.

41. If MHC-I molecules are expressed on the cell, the killer-inhibitory receptor sends a negative signal that overrides the kill signal and prevents the NK cell from killing that cell.
Without the signal from the killer-inhibitory receptor, the kill signal from the killer-activating signal is not overridden and the NK cell kills the cell to which it has bound.

43. NK cells lyse "foreign" cells by inserting pore-forming molecule perforin into their membranes (in a manner similar to CTLs and MAC of the complement pathway) and injecting Cytotoxic granzymes.

45. Stimulating Cells to Secrete variety of Cytokines
Cytokines are low molecular weight, soluble proteins that function as chemical messengers for regulating the immune system.
They are produced by all cells involved in innate and adaptive immunity especially by T helper (Th) lymphocytes.
The activation of cytokine-producing cells triggers them to synthesize and secrete their cytokines

46. The cytokines, in turn, are then able to bind to specific cytokine receptors on other cells of the immune system and influence their activity in some manner.
Interleukin-1 (IL-1), 2, 3, 4…….
Interferons (IFN).

47. Interleukin-1 (IL-1)
ActivatesT4-lymphocytes, B-lymphocytes, NK cells, polymorphonuclear leukocytes.
Stimulates the synthesis of adhesion factors on endothelial cells and leukocytes for diapedesis.
Activates macrophages; promotes inflammation.
Produced by monocytes, macrophages, dendritic cells.

48. Interleukin-2 (IL-2)
Growth and differentiation factor for T4-lymphocytes, T8-lymphocytes, B-lymphocytes, and NK cells.
Promotes antibody secretion by B-lymphocytes.
Activates cytotoxic T-lymphocytes, NK cells and monocytes/macrophages.
Produced by activated T4-lymphocytes.

49. Interferons (IFN)
Interferons modulate the activity of virtually every component of the immune system.
Type I interferons include more than 20 types of interferon-alpha, interferon-beta and interferon omega.
There is only one type II interferon, interferon-gamma

50. Type I interferons, which can be produced by virtually any virus-infected cell is better able to induce viral resistance in cells.
where as type II interferon is produced by activated T-lymphocytes as part of an immune response and functions mainly to promote the activity of the components of the cell-mediated immune system such as CTLs, macrophages, and NK cells

51. Interferons induce uninfected cells to produce enzymes capable of degrading mRNA.
These enzymes remain inactive until the uninfected cell becomes infected with a virus.
At this point, the enzymes are activated and begin to degrade both viral and cellular mRNA.
This not only blocks viral protein synthesis, it also eventually kills the infected cell.

53. Thanks