The cell-mediated immunity (CMI) is regarded as the main mechanism of protection and clearance against intracellular infectious agents and particularly against viral infections.
With this target, the TLR-mediated activation of innate effector cells generates a Thelper1 (Th1) response characterized by the activation of cytotoxic T lymphocytes (CTL) and of an inflammatory response.
Cell-mediated immunity is triggered when antigen is presented by antigen presenting cell (APC) and recognized by pathogen-specific T lymphocyte and the clonal expansion and activation of antigen specific Th1 and CTL occurs.
During the cell-mediated immunity against viruses, the APCs are myeloid dendritic cells (mDc) expressing TLR3 and producing IL-12.
The onset of a Th1 response requires the activation of dendritic cells in response to tissue damage and the activation of inflammatory/innate cells with secretion of Type 1 Interferons (against viruses), IL-1, TNFα, IL-8 and IL-6. The concurrent stimulation of the same TLRs (TLR3 and TLR 7 during viral infection), expressed on both NK and DC cells, has a key role in their mutual activation, in the production of this cytokine pattern.
This represents a crucial point of connection between innate and adaptive immunity making the dendritic cell able to finalize the response towards Th1.
Th1 immunity activates some effector mechanisms of the innate immunity against the target antigens in a more effective way. By means of cytokine secretion (mainly IFNγ), it triggers the killing of infected cells by macrophages and by NK cells, while specific antibodies activate classical complement pathway and/or activate ADCC (Antibody-Dependent Cellular Citotoxicity) reaction and phagocytosis. Specifically, the cellular effector response against intracellular microorganisms (viruses, intracellular bacteria and protozoa) is based on the killing and elimination of the infected cell and is ultimately conducted by:
- Specific cytotoxic T lymphocytes (CTL) that kill, by apoptosis, infected cells by promoting clearance of the virus in the primary response and establish a specific memory permitting the elimination of the infection. The action of CTLs occurs through the induction of apoptosis into the target cell by secretion of so called “perforin proteins” that form pores in the cell membrane and allow the entry of granzimes, with the induction of programmed cell death as well as the expression of the ligand Fas that binds to the surface Fas molecules on target cell inducing death signals.
- NK cells kill cells infected by viruses either directly or through the binding of antibodies (ADCC reactions). Their action is inhibited by the binding to the high molecular MHC I molecules on healthy cells while they exert cytotoxicity against cells expressing a reduced or absent class I MHC expression (a mechanism by which viruses try to evade the action of CTLs).
- Inflammatory macrophages activated by IFN-γ, which recognize and phagocyte apoptotic cells after the cytotoxicity of CTL and NK; they also can produce TNFα inducing apoptosis.
Furthermore, B-cells IgG (specially IgG2a) isotype switching is promoted by IFN-γ, the prototypical Th1 cytokine. In fact, during CMI, an effector response mediated by antibodies is triggered against infected cells and is based also against intracellular bacteria/virus:
- Neutralizing antibodies to pathogens
- Complement-fixation antibodies with opsonization and phagocytosis of the pathogen
- Antibodies that activate the membrane attack complex complement determining virolysis on direct cytotoxicity of infected cells
- Antibodies mediating ADCC reactions against infected cells
Phagocytosis of the immune complex (antibody-pathogen) is performed by inflammatory phagocytes in the first instance by neutrophils and subsequently by monocytes/macrophages recruited by chemokines (IL-8, MCP1).
Although antibodies can neutralize extracellular phase virions and kill infected cells, the cell-mediated immunity plays a key role in controlling viral infections and cytotoxicity mediated by T lymphocytes is the main mechanism.
In summary, the activation of a CMI response requires an inborn innate immunity with an early innate cell activation mediated by the recognition of "danger" signals by innate sensors (TLRs, complement, Acute Phase Proteins) and an optimal production of IFN α / β and IL-1, TNFα, IL-8 and IL-6.
So, the basic mechanisms connecting innate and acquired immunity are:
- The co-operation between NK-DCs-macrophage with reciprocal activation and production of IFN-γ, IL-12 and IL-15
- Maturation / activation of mDC acting as APC
- IL-12 and IFN-γ produced by the innate immune cells trigger the Th1 response that supports the cell-mediated specific immune response
- The CD4 + Th1 activated by IFN-γ and IL-2 secretion, stimulate the effective functions of NK and macrophage cells and subsequently specific cytotoxic T lymphocytes (CTLs) that complement the viral clearance and create cytotoxic memory