Initiation of cell-mediated immune response
For adaptive immunity to come into play, the mere recognition of a foreign antigen is not enough. An additional danger signal is required, a role played by PAMP (pathogen-associated molecular patterns). If an antigen enters the body in isolation, without PAMP (as happens with food proteins), anergy develops—an active form of specific tolerance.
The initiation of the response is impossible without the involvement of innate immunity factors. It begins with antigen-presenting cells (APCs) demonstrating foreign epitopes to naive T lymphocytes. At the same time, APCs must provide co-stimulation via special surface molecules. Only after receiving both signals does the proliferative expansion of specific T cell clones begin.
The choice of a specific pathway for the response depends on the pathogen's localization, its properties, and interaction with the first-line defense cells. The success of infection elimination directly depends on how correctly the body chooses the form of the response.
Two variants of cellular defense
Cell-mediated immunity takes over when the pathogen hides inside cells and is inaccessible to antibodies. Depending on the exact location of the pathogen, the immune system implements one of two strategies:
- Inflammatory cell-mediated response. Activated against microbes surviving inside macrophage endosomes or granules (e.g., mycobacteria). The main regulators here are Th1 lymphocytes (CD4+). They recognize the antigen in complex with MHC-II. Upon contact, Th1 secretes IFNγ and interacts with the macrophage via CD154 molecules (on the T cell) and CD40 (on the macrophage). This leads to potent macrophage activation: inducible NO synthase is expressed within it, nitric oxide is produced, and the intracellular pathogen is destroyed.
- Cytotoxic cell-mediated response. Used if the pathogen is localized directly in the cytosol or the viral genome is integrated into the cell's DNA. Since the cell cannot be "cured," it must be radically destroyed. This task is performed by cytotoxic CD8+ T lymphocytes (cytotoxic T cells). They recognize peptides in the context of MHC-I. To kill the target, cytotoxic T cells release perforin and granzyme B, and also use a contact-dependent mechanism (Fas/FasL interaction).
Summary table: Choosing an immune response
| Pathogen localization | Presentation | T cells | Response variant | Effector mechanism |
|---|---|---|---|---|
| Intracellular (granules) | MHC-II | Th1 (CD4+) | Inflammatory | Activation of macrophage bactericidal activity |
| Intracellular (cytosol) | MHC-I | CD8+ lymphocytes | Cytotoxic | Contact-dependent cytolysis of the infected cell |
Role of Th17 lymphocytes
During the development of the cell-mediated response, other populations of effector cells can also form, in particular Th17 lymphocytes. They got their name from their dominant secretion product—the cytokine IL-17.
The main physiological function of Th17 cells is the recruitment and activation of neutrophils, as well as the protection and repair of epithelial barriers. However, the clinical significance of this subpopulation is often associated with pathology: excessive or inadequate activity of Th17 lymphocytes plays a key role in triggering autoimmune processes.
Phases of the immune response
Any immune response, including cell-mediated, is not instantaneous because its components are not pre-formed, but generated de novo. The process is divided into two main phases:
- Inductive phase. Includes antigen recognition, its presentation, and subsequent differentiation of naive T lymphocytes into effector cells.
- Effector phase. Begins about a week later. This is the period of direct execution of defense reactions and destruction of pathogens.
After the foreign agent is completely eliminated, regulatory mechanisms are triggered to limit inflammation. Immunological memory of the contact is preserved in the form of circulating memory T cells, due to which a secondary response to the same antigen will develop much faster.
Briefly: answers to topical questions
What cytokines, besides interferon-gamma, do Th1-lymphocytes secrete?
In addition to interferon-gamma, Th1 lymphocytes secrete a number of other cytokines that ensure their effector functions. These include:
- Interleukin-2 (IL-2)
- Interleukin-3 (IL-3)
- Tumor necrosis factor alpha (TNFα)
- Tumor necrosis factor beta / Lymphotoxin alpha (TNFβ / Lymphotoxin α)
- Granulocyte-macrophage colony-stimulating factor (GM-CSF)
These cytokines make a significant contribution to Th1 cell activity, although their production may not be strictly specific to this subpopulation alone.
How does intracellular antigen processing occur for presentation in complex with MHC-I?
Intracellular antigen processing for presentation in the context of MHC-I involves protein cleavage and peptide transport. The process consists of the following stages:
- Antigen cleavage — occurs in the cell cytosol involving the proteasome (or immunoproteasome).
- Peptide transport — fragments are transferred from the cytoplasm to the endoplasmic reticulum (ER) using TAP transporter systems.
- Complex assembly — in the ER, the MHC-I α-chain joins with β2-microglobulin. The empty molecule is temporarily stabilized by chaperones (calnexin and calreticulin).
- Peptide loading — delivered peptides are embedded into the peptide-binding groove of the MHC-I molecule, after which the chaperones dissociate.
What surface markers (CD receptors) are characteristic of mature cytotoxic T lymphocytes?
Mature cytotoxic T lymphocytes are characterized by the presence of a specific set of surface CD markers. The main receptors include:
- CD8 — a co-receptor represented by a dimer (often CD8αβ), participating in antigen recognition in the context of MHC-I.
- CD3 — a complex that is part of the T-cell receptor (TCR) and performs a signaling function.
- CD2 — a marker that persists at all stages of T-cell development.
- CD5 and CD28 — molecules whose expression begins at the double-positive cell stage and persists on mature lymphocytes.
- CD44 — expressed on mature single-positive cells (CD44+ CD25- phenotype).
Which specific receptors and ligands provide co-stimulation of T lymphocytes upon contact with an antigen-presenting cell?
Co-stimulation of T lymphocytes upon contact with an antigen-presenting cell (APC) is provided by specific pairs of activating receptors and ligands. These include:
- CD28 — a receptor on T cells that binds to CD80 (B7-1) and CD86 (B7-2) ligands on the surface of the APC. This is the best-known and most important co-stimulation system, ensuring IL-2 secretion.
- ICOS — a receptor on activated T cells that interacts with the ICOSL ligand on the APC. It provides co-stimulation and cytokine secretion.
There are also suppressory pathways (involving CTLA-4 and PD-1 receptors) that inhibit the immune response by binding to the same or related ligands.
Class and exam questions
Why is the humoral immunity (antibodies) ineffective against intracellular infections?
Antibodies are large protein molecules that are physically unable to penetrate the membrane into living cells. Therefore, they cannot reach viruses or bacteria hiding in the cytosol or endosomes.
What is the difference between cytotoxic T cells (CD8+) and natural killer (NK) cells?
Although their mechanism of cytolysis (target cell destruction) is very similar, cytotoxic T cells have strict antigenic specificity and recognize specific peptides. NK cells belong to the innate immunity and act less selectively.
What happens if antigen presentation occurs without co-stimulation?
If a dendritic cell presents an antigen to a T lymphocyte without additional co-stimulatory signals (which appear in the presence of PAMPs), the immune response will not be triggered, and anergy (unresponsiveness) will develop instead.
What else to study on this topic
- Humoral immune response and Th2 cell functions
- Opsonization mechanisms and the role of the complement system
- Immunity against extracellular macroparasites (helminths)
- The role of interleukin-13 (IL-13) in allergic reactions
- Mechanisms of induction and overcoming of immunological tolerance
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