The term cell-mediated immune response (CMI) refers to destruction of cells carrying intracellular microbes and other abnormal cells, such as tumor cells by various specific and nonspecific cells of immune system, of which the most important is cytotoxic T (T_C ) cells.

Role of CMI

CMI mediates the following immunological functions:

* Provides immunity against microbes residing in intracellular milieu:

- For obligate intracellular organisms, CMI remains the only effective immune response. Examples include all viruses, some bacteria (Mycobacterium, Chlamydia and Rickettsia), some parasites (Plasmodium, Leishmania, Trypanosoma and Cryptosporidium) and some fungi (Pneumocystis)

- For facultative intracellular organisms, humoral immunity is active as long as the organism is extracellular. Once they come to intracellular milieu, CMI takes the leading role. Examples include Bacteria like Listeria, Salmonella and Yersinia and fungi such as Histoplasma and Cryptococcus.

* Provides immunity against tumor cells and other damaged and altered cells

* Mediates delayed hypersensitivity (type IV hypersensitivity)

*Plays key role in transplantation immunity and graft versus-host (GVH) reaction.

Effector Cells of CMI

CMI can be mediated by both antigen specific and nonspecific effector cells (Table 1). They perform their function by direct killing of the target cells (e.g. virus infected cells or tumor cells).

* The most important mediator of CMI is cytotoxic T cell which is antigen specific

* However, many other nonspecific effector cells such as macrophages, NK cells, neutrophils, and eosinophils also contribute to CMI

* Although CMI has many features distinct from humoral immune response but it is not completely independent. The nonspecific effector cells use antibodies as receptors to recognize the target cells for killing.

Table1. effector cells of CMI.

Cytotoxic T Lymphocytes

 CD8 cytotoxic T lymphocytes (CTL or T_C ) are the principal effector cells of CMI, involved in the destruction of target cells such as virus infected host cells and tumor cells. Naive T_C cells (or CTL precursors) respond to viral or tumor peptide antigens which are processed by the target host cells (by cytosolic pathway) and presented along with MHC class I molecules. Activated T_C in turn secretes cytotoxic enzymes that lyse the target cells.

Activation of CTL

Generation of activated CTL from naive T_C cells requires induction of at least three signals (Fig. 1):

1. Antigen-specific signal: It is induced by binding of TCR-CD3 complex of naive T_C cells to MHC I-peptide complex of target cells. CD8 of T_C cells also interacts with α3 domain of MHC-I

 2. Costimulatory signal: CD28 of naive T_C cells interacts with B7 molecule on target cells

3. Third signal: IL-2 (secreted by TH 1 cell) acts on high affinity IL-2 receptor on TC cells.

 Following induction, the transmission of signal occurs in a way similar to that described for T_H cells.

Fig1. Activation and differentiation of T_C cells.

Functions of CTL (target Cell Lysis)

The activated TC cells produce two types of lethal enzymes; called perforins and granzymes.

* Perforins produce pores in the target cell membrane; through which granzymes are released inside

* Granzymes are serine proteases; they induce cell death by apoptosis through caspase pathway.

Natural Killer Cells

 Natural killer cells are large granular lymphocytes that constitute 10–15% of peripheral blood lymphocytes.

* They are derived from a separate lymphoid lineage. NK cells are cytotoxic, but antigen nonspecific

* They are part of innate immunity, act as first line of defense and do not require prior contact with the antigen.

 NK cells act against virus infected cells and tumor cells till the TC cells are activated and take over the function.

However, they differ from TC cells in many other aspects (Table 2) such as:

* Natural killer cell markers: NK cells lack the T cell markers such as CD3, CD4 or CD8 molecules (hence are also called null cells), instead possess specific surface markers such as CD16 and CD56

* No MHC restriction: NK cells can recognize the ligands (antigens) without MHC presentation

* Innate immunity: NK cells are part of innate immunity; they do not require the prior exposure to microbial antigen

* No memory: NK cells do not differentiate into memory cells.

Table2. Comparison between NK cells and Tc cells.

Mechanism of NK Cell-mediated Cytotoxicity

Receptor Interaction

 Natural killer cells are not MHC restricted. They directly recognize certain ligands (e.g. glycoproteins) present on the surface of altered host cells like virus-infected cells or tumor cells. However, such ligands are also present on normal cells. Still, NK cells are capable of distinguishing normal host cells from the altered cells (Figs2A and B). This is mediated by two types of receptors present on NK cell surface (theory of opposing-signals model).

* Activation receptors (e.g. NKR-P1, CD16): When these receptors are engaged with ligands present on the target cells; NK cells become activated

 Inhibitory receptors (such as C-type lectin inhibitory receptors): They recognize a part of MHC I molecule (HLA-E) which is present on the surface of all normal nucleated cells

- Binding of inhibitory receptors to MHC-I molecules generates an inhibitory signal that suppresses the NK cells even if they are bound to the activation receptors. This is because the inhibitory signal is the dominant signal and hence it overrides the activation signal

- However, in virus infected cells and tumor cells, the MHC-I expression is remarkably reduced. In such cases, there would not be any inhibitory signal.

Hence, binding of activation receptor to its ligand leads to activation of NK cells.

Fig2 A and B: NK cell-mediated cytotoxicity: A. In normal cell; B. In virus infected cell.

Target Cell Destruction

 Mechanism of target cell lysis by NK cells is similar to that of TC cells, i.e. via secreting perforins and granzymes. Perforins form pores on target cells, through which granzymes enter and lyse the target cells (Fig. 2B). The only difference is that, the enzymes are constitutively expressed in NK cell cytoplasm (i.e. they are cytotoxic all the time, even without exposure to the antigen).

Alternative Mechanisms of NK Cell Activity

* NK cells respond to IL-12 produced by macrophages and secrete IFN-γ, which in turn activates the macrophages. T hen, the activated macrophages phagocytose and kill the microbes

* NK cells also mediate their function via ADCC (described below).

Antibody-dependent Cell-mediated Cytotoxicity (ADCC)

 A number of nonspecific cytotoxic cells express receptors (FcR) on their surface that can bind to the Fc region of any immunoglobulin.

* Following contact with a target cell coated with an antibody, these FcR bearing cells can bind to Fc portion of the antibody coated on the target cells, and subsequently cause lysis of the target cell

* Although these cytotoxic cells are nonspecific for the antigen, the specificity of the antibody directs them towards the specific target cells. This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC).

 ADCC is exhibited by various cells such as NK cells, macrophages, monocytes, neutrophils, and eosinophils.

They release various cytotoxic factors into the target cells like perforins, granzymes, lytic enzymes, free radicals, TNF, etc. (Fig. 3). However, there is no complement dependent cytolytic activity.

* NK cells secrete perforins, and granzymes. Neutrophils release lytic enzymes

* Eosinophils can release lytic enzymes and perforins; play an important role in providing immunity against helminths

* Macrophages produce lytic enzymes and TNF.

Fig3. Cytotoxic factors released by various cells in ADCC.

 Assessment/Detection of CMI

There are several methods for detection of CMI.

* The mixed-lymphocyte reaction (MLR) is an in vitro system for assaying T cell proliferation in a cell-mediated response

* Cell-mediated lympholysis (CML) is another in vitro assay for testing the cytotoxic function of effector cells of CMI

* The graft-versus-host (GVH) reaction in experimental animals provides an in vivo system for studying cell mediated cytotoxicity.

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مواضيع ذات صلة

Hypersensitivity Reactions

Humoral/Antibody-Mediated Immune Response

Helper T Cells (Activation AND Differentiation)

Type III (Immune Complex) Reactions

Influenza virus immunology

Type II Antibody-Dependent, Complement-Mediated Cytotoxic Reactions

Immunologic Manifestations of Rubella infection

Antigen presentation

Cytokines

Structure of MHC Molecule

MHC Genes and Their Products

Macrophage