Main stages of the response development
The process of the cellular immune response takes place in barrier tissues and secondary lymphoid organs in 4 stages:
- Antigen presentation. A dendritic cell (DC) engulfs the pathogen, migrates to a regional lymph node, and presents the antigen to CD4+ T lymphocytes, inducing their primary activation.
- Th1 cell development. Under the influence of IL-12 from dendritic cells and IFNγ (initially secreted by NK and NKT cells), activated CD4+ cells differentiate into effector Th1 lymphocytes. At the same time, their conversion into Th2 cells is blocked.
- Macrophage activation. Specific Th1 lymphocytes enter the bloodstream and migrate to the site of inflammation, where they interact with macrophages via the cytokine IFNγ.
- Effector phase. Macrophages activate phagocytosis, break down intracellular pathogens, and release their own cytokines.
Phenotype switch and migration of Th1 cells
To reach the site of infection, a Th1 lymphocyte must alter its set of membrane receptors. It acquires effector cell properties:
- Loses the CD62L and CCR7 molecules that previously enabled its return to secondary lymphoid organs (a similar process is characteristic of cytotoxic T lymphocytes).
- Acquires membrane integrins LFA-1 and VLA-4, as well as specific chemokine receptors (CXCR3, CCR5, CCR2) sensitive to signals from the site of inflammation.
Macrophage stimulation mechanisms
Upon encountering a macrophage bearing MHC-II molecules with a peptide antigen, a Th1 cell forms an immune synapse with it. At this moment, the T cell receives a secondary signal via TCR/CD4 and CD28. Macrophage stimulation is realized through two parallel pathways:
- Contact-dependent mechanism: mediated via the CD40 molecule on the macrophage and its ligand CD154, which is expressed on the Th1 cell only as a result of synapse formation. The signal is transmitted inside via adaptor proteins TRAF-1, 2, 6, activating the NF-κB factor and the Rac-dependent MAP kinase cascade, leading to the formation of the c-Jun transcription factor.
- Cytokine mechanism: Th1 cells directionally (strictly into the synapse) secrete IFNγ. The binding of the cytokine to its receptor engages kinases Jak1 and Jak2, activating the transcription factor STAT1.
Activation effects and the IL-12 / IFNγ integrated system
As a result of activation, the macrophage increases the expression of MHC-I and MHC-II molecules, assembles NADPH oxidase, and activates oxidative metabolism. The most specific marker of IFNγ action is the expression of the inducible NO synthase (iNOS) gene, leading to the release of nitric oxide and superoxide anion.
IFNγ and IL-12 form a unified regulatory loop:
- Binding of PAMPs to TLR receptors on macrophages (via the MyD88 adaptor and NF-κB factor) triggers the production of IL-12 by macrophages.
- IL-12 induces Th1 cells to produce IFNγ.
- IFNγ acts on macrophages, further enhancing their synthesis of IL-12 (positive feedback).
Granuloma formation
If the cellular response is ineffective and macrophages cannot destroy intracellular bacteria, a granuloma forms in the tissues—a rounded structure that isolates the pathogen.
- Center: infected macrophages, cellular debris, and released pathogens.
- Specific zone: transformed macrophages—epithelioid and multinucleated giant cells (resulting from fusion).
- Periphery: an accumulation of activated uninfected macrophages and Th1 lymphocytes.
Cells within the granuloma retain mobility to maintain its integrity. However, this protective mechanism inevitably leads to the destruction of host tissues and impaired organ function.
The opposite: Th2-mediated cellular response
Unlike the inflammatory Th1 response, Th2 lymphocytes are directed against multicellular parasites (helminths). Their main targets are eosinophils and mast cells. The key cytokine IL-5 attracts eosinophils, which degranulate, releasing parasite-toxic proteins: major basic protein (MBP), eosinophil peroxidase (EPO), and eosinophil cationic protein (ECP). In addition, IgE antibodies bind to high-affinity FcεRI receptors on mast cells, conferring anti-parasitic precision to their action.
Briefly: answers to topical questions
Which transcription factors are required for the differentiation of naive CD4+ T cells into Th1 lymphocytes?
For the differentiation of CD4+ T cells into Th1 lymphocytes, sources indicate the following transcription and signaling factors:
- T-bet — the key transcription factor for Th1; its expression correlates with IFNγ production and participates in stabilizing the Th1 phenotype.
- STAT1 — activated when IFNγ binds to IFNγR and stimulates T-bet.
- STAT4 — activated when IL-12 binds to the IL-12Rβ1β2 receptor.
- Hlx, ERM, IRF-1 — additional Th1 differentiation factors.
Which cytokines, besides IL-12 and IFNγ, are involved in the Th1 polarization of T helper cells?
Besides IL-12 and IFNγ, sources indicate the following cytokines involved in Th1 polarization of T helper cells:
- IL-18, IL-23, IL-27 — sustaining factors for Th1 cell differentiation.
- TNFα, TGFβ, IFNα — secondary factors for Th1 cell differentiation.
- IFNα/β — part of the cytokine cocktail secreted by dendritic cells upon interaction with activated Th0 lymphocytes to promote Th1 development.
Dendritic cells are the primary source of cytokines for Th1 cell differentiation; upon interaction with activated Th0 lymphocytes, they secrete IL-12, IFNγ, IL-18, IL-23, IL-27, and IFNα/β.
Class and exam questions
Why do host tissues get damaged during a Th1-mediated cellular response?
After physical contact at the synapse ceases, the macrophage releases bactericidal factors (reactive oxygen species, NO, enzymes) non-selectively into the extracellular environment, acidifying it and destroying surrounding normal cells.
What is the synergism of cytokines in macrophage activation?
The bactericidal effects of interferon-gamma (IFNγ), especially the induction of NO synthase, are multifold enhanced by the action of tumor necrosis factor (TNFα), which is produced by both T cells and macrophages.
What are the consequences of receptor defects in the IL-12/IFNγ system?
Defects in any link of this functional system lead to severe immunodeficiencies. The body loses the ability to activate macrophages, which clinically manifests as extreme susceptibility to mycobacteria.
What is the role of the humoral immune response?
Unlike the cellular response, the humoral response (involving B lymphocytes and Th2 cells) is designed to block extracellular pathogens through the production of antibodies. B cells undergo 4 stages: from antigenic stimulation to differentiation into plasma cells and memory cells.
What else to study on this topic
- Mechanisms of signal transduction via TRAF proteins and NF-κB activation
- The role of the Jak-STAT cascade in cytokine stimulation of macrophages
- Biochemical pathways of peroxynitrite and free radical generation
- Detailed structure of the immune synapse
- Molecular stages of B-cell receptor isotype switching
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