Evolutionary separation and synergy of immune branches
Historically, the immune system is divided into two components. The ancient component — innate immunity — relies on the recognition of pathogen-associated molecular patterns (foreign microbial molecules). The main tool of this branch is phagocytosis. In addition, it is able to respond to endogenous danger signals, which is critically important for defense against transformed (tumor) cells.
A later evolutionary acquisition is adaptive immunity. It recognizes individual macromolecules (antigens) with extremely high specificity. Both systems work in close coordination:
- Effect of innate on adaptive: The processes of antigen presentation and co-stimulation, provided by first-line defense cells, are absolutely essential for initiating an adaptive response.
- Effect of adaptive on innate: Specific immunity practically lacks its own effector mechanisms. By producing antibodies and cytokines, it redirects innate immune mechanisms, imparts selectivity of action, and dramatically increases their destructive efficacy through contact interactions.
Immunological memory: solving the problem of short-lived effectors
Initially, protective immunity relies on effector factors: cytotoxic T lymphocytes, antibodies, and activated cells. However, the lifespan of these factors is strictly limited. To maintain body resistance after pathogen eradication (elimination), the system generates memory cells.
They are formed during the primary immune response simultaneously with effector cells, but are not involved in the ongoing fight. Their sole task is protection upon re-exposure to the same antigen.
How memory cells differ from naïve lymphocytes:
- Quantitative advantage: The size of the memory clone is 100–1000 times (2–3 orders of magnitude) larger than the pool of lymphocytes that have not yet encountered the antigen.
- Qualitative preparation of B cells: They have already undergone antibody isotype switching, and their immunoglobulin genes contain somatic mutations (resulting from processes in germinal centers) for maximal affinity.
- Qualitative preparation of T cells (CD4+): They are already differentiated into specialized subpopulations (e.g., Th1, Th2, Th17).
Externally (morphologically), memory cells are indistinguishable from naïve cells, but they possess a distinct set of surface markers. These markers determine their specific recirculation pathways in the body. The result of their activity is a significantly faster secondary immune response, although the exact nature of their enhanced efficacy is not yet fully understood.
Chronology of the immune response
The development of adaptive defense following a pathogen invasion follows a clear timeline:
- Inductive phase: Takes place during the first week (0–1 week).
- Effector phase: Lasts from the 1st to the 3rd week. During this period, cytotoxic T lymphocytes reach peak activity, and delayed-type hypersensitivity (DTH) effector mechanisms are triggered.
- Antibody synthesis and protection: Antibody production and the formation of direct protective immunity begin from the 1st week. Antibodies can circulate in the blood for many years.
- Memory formation: The pool of memory cells finally forms by the 3rd–4th week and persists for years, effectively preventing disease development upon reinfection.
Practical application: from prevention to treatment
Traditional vaccination is the main direction of practical immunology. Its essence lies in inducing effective immunological memory without clinical manifestations of the disease itself.
However, modern vaccination principles have gone further and are now used for therapeutic (treatment) purposes. Tumor vaccines, allergy vaccines, and drugs for treating autoimmune diseases are being developed. Their main task is not just to form memory, but to purposefully redirect the immune response:
- In allergies: An attempt to induce a Th1-mediated response to the allergen in order to suppress the already established pathological Th2 response causing symptoms.
- In autoimmune processes: An attempt to induce a state of anergy (tolerance, unresponsiveness) to self-autoantigens.
- In tumors: Enhancement of the immune response against tumor antigens and its redirection strictly along the Th1 pathway for efficient destruction of transformed cells.
Briefly: answers to topical questions
What surface CD markers distinguish memory T cells from naïve T lymphocytes?
The main difference between memory T cells and naïve T lymphocytes is the expression of a shortened isoform of the CD45 molecule.
- Naïve T cells express the long CD45RA isoform, as well as high levels of L-selectin (CD62L) and the chemokine receptor CCR7.
- Memory T cells express the shortened CD45R0 variant, generated through alternative RNA splicing.
The CD45R0 molecule is not an absolute reliable marker, as it can eventually be replaced by the original CD45RA variant.
Which professional antigen-presenting cells (APCs) initiate adaptive immunity?
The primary adaptive immune response is initiated exclusively by dendritic cells, although three types of cells are classified as professional APCs.
- Dendritic cells are the only APCs capable of effectively activating naïve T lymphocytes. Their presentation potential is 100 times greater than that of macrophages.
- Macrophages activate effector T cells and memory cells.
- B lymphocytes activate helper T lymphocytes (effector and memory).
Thus, only dendritic cells and CD4+ T helpers participate in the initiation of the primary response.
What pattern-recognition receptors does innate immunity use to detect foreign microbial molecules?
To detect foreign molecules (PAMPs), innate immune cells use several groups of pattern-recognition receptors (PRRs).
- Toll-like receptors (TLRs) are the main drivers of myeloid cell activation (e.g., TLR-2, TLR-4, TLR-3).
- Nod-like receptors (NLRs) are cytosolic receptors (including NALPs) involved in inflammasome formation.
- C-type lectin receptors — for example, Dectin-1, which binds yeast β-glucans.
Integrins can also act as co-receptors, promoting the activation of transcription factors NF-κB and AP-1.
What cytokines and mechanisms ensure the development of delayed-type hypersensitivity (DTH) during the effector phase?
The development of the DTH effector phase is ensured by the interaction of Th1 cells with macrophages via contact and humoral mechanisms.
- Humoral mechanism — activated Th1 cells release MCF and MIF factors to recruit macrophages and secrete the main effector cytokine, interferon-gamma (IFNγ).
- Contact mechanism — mediated through the binding of the CD154 molecule on the T cell to the CD40 receptor on the macrophage surface.
As a result, macrophages are activated and release proinflammatory cytokines, oxidative burst products, nitrogen metabolites, and hydrolases.
What is the function of co-stimulatory signals during the interaction between innate immune cells and lymphocytes?
The main function of co-stimulatory signals is to enhance the specific signal from the antigen-recognition complex for full lymphocyte activation. Co-stimulation is a mandatory component of antigen presentation. The interaction of co-stimulatory molecules (e.g., CD80/CD86 on APCs and CD28 on T cells) ensures the transmission of an additional activating signal. Antigen recognition in the absence of a co-stimulatory signal does not lead to activation, but induces functional inactivation — T-cell anergy, which serves as an important mechanism for maintaining self-tolerance.
Class and exam questions
Can adaptive immunity launch independently, without the participation of innate immunity?
No, this is impossible. To initiate an adaptive response, lymphocytes critically require antigen presentation and co-stimulatory signals from innate immune cells.
What is the main function of the effector mechanisms of adaptive immunity?
Adaptive immunity has virtually no effector mechanisms of its own. Its main function is to use antibodies and cytokines to impart specificity to innate immune mechanisms and dramatically increase their efficiency.
Do memory cells participate in the primary immune response?
No. Although they are generated during the primary response simultaneously with effector cells, they are not involved in the current destruction of the pathogen, being preserved exclusively for defense upon re-exposure to the antigen.
What else to study on this topic
- Mechanisms of antigen presentation and co-stimulation
- Somatic hypermutation processes in germinal centers of follicles
- Subpopulations of CD4+ T lymphocytes (Th1, Th2, Th17) and their cytokine profiles
- Endogenous danger signals in antitumor immunity
- Mechanisms of delayed-type hypersensitivity (DTH)
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