CELL-MEDIATED IMMUNITY

 

CELL-MEDIATED IMMUNITY

—  CMI is an immune response that involves activation of:  Cells

—  Cytotoxic T-lymphocytes

—  Macrophage

—  Natural killer cell,

—   Release of various cytokines in response to an antigen.

 Cytotoxic T-cell

—  It is most effective in removing virus-infected cells, tumour cells, and intracellular bacteria.

—  It also plays a major role in transplant rejection.

—  In periphery, when cytotoxic T-cell is required Pre-CTL is activated by T-helper cell

—  T-helper cell is primed to respond to viral peptides after viral particles have been ingested and presented by MQ cells at the site of infection.

—  .

—  Antigens inside a cell are brought to the surface of the APC by the class II MHC molecule, where they can be recognized by the T helper cell

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—  In turn the activated helper T-cell activates virus-specific CTL

the CD4⁺ helper T cells gives a potent activating signal to the naive CD8⁺ T cells Once activated, the CTL cell undergoes clonal expansion with the help of the cytokine Interleukin-2 (IL-2), which is a growth and differentiation factor for T cells.

—  IFN-γ and IL-6 stimulators of CTL

—  IFN-γ-has antiviral activity

—  Two ways to kill target cell

       1. CTL release perforin which polymerises in the presence of Calcium ions to form a hollow                tube (analogous to MAC of complement system (C9 resembles perforin).

—  If sufficient number of pores are formed, the cell is killed by osmotic lysis

2. CTL release lymphotoxin which has active enzymes released into the target cell to cleave DNA in the nucleus, results in clumps of nuclear DNA each of a small uniform length-hence programmed cell death or apoptosis

3. Disengagement of CTL - CTL are protected from action of their own granule content by high concentration of protectins (disassembling protein on the surface)

—  killing requires cell to cell contact

—  Only cells to which a CTL becomes attached are killed

—  CTLs are not themselves damaged during the process

 

Natural Killer cell

—  The role of NK cells is analogous to that of cytotoxic T cells in the  adaptive immune response.

—  NK cells provide rapid responses to virus-infected cells, and respond to tumor formation.

—  NK cells are unique, however, as they have the ability to recognize and kill infected cells in the absence MHC class 1, allowing for a much faster immune reaction.

—  This role is NB because infected cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

—  NKC usually express the surface markers CD16 (FcγRIII)

 

Antibody-dependent cell-mediated cytotoxicity (ADCC)

1.     Infected cells are opsonized with antibodies for detection by immune cells.

Antibodies that bind to antigens can be recognised by FcγRIII (CD16) receptors expressed on NK cells,

Resulting in NK activation, release of cytolytic granules and consequent cell apoptosis.

This is a major killing mechanism of some  Mabs  like  rituximab), ofatumumab

 

Activated NK cells are cytotoxic; small granules in their cytoplasm contain proteins such as perforin and proteases (as granzymes).

Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the perforin and proteases can enter, inducing osmotic cell lysis.

 

MACROPHAGE

—  are a type of white blood cell of the immune system that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, in a process called phagocytosis

—  Cytotoxicity may be triggered specifically to a target ADCC or may involve non-specific toxic mediators

—  MQ expresses FCYR1, which allow them to engage tumours by ADCC

—  MQ destroy pathogen by internalizing them and subjecting them to toxic molecules and enzymes within the phagolysosome

—  These include

—  Reactive oxygen intermediates, toxic oxidants and nitric oxide

—  If the phagocyte fails to internalize the target, then these mediators maybe released into the extracellullar environment and contribute to local cell damage-this is frustrated phagocytosis

—   occurs when the target is engaged by surface receptors, but it too large to phagocytose

—  The action of mediators produced by the phagocyte damage the target rather than induce apoptosis and leads to necrosis and inflammation

—  Activated macrophage produce TNF which induces apoptosis in a similar way to CTL and NK cells

—  Other cells; mast, eosinophils, neutrophils and basophils