Cell-Mediated Immunity: T Cell Subsets, Effector Mechanisms, and Clinical Importance

An organ transplant can fail even when the surgery is perfect and the blood types match. A person with well-controlled HIV can suddenly develop shingles, or a brain infection from a parasite they caught harmlessly years ago.

The thread connecting all three is cell-mediated immunity: the arm of the immune system that deals with threats hiding inside cells. When it works, it silently clears virus-infected cells, tumor cells, and intracellular bacteria. When it fails, a specific and predictable set of infections and complications appears. This article covers what cell-mediated immunity does, how its cells kill, and what its loss reveals about why it matters.

Cell-mediated immunity is one of two arms of adaptive immunity, the other being humoral or antibody-mediated immunity. Cell-mediated immunity (CMI) is a complex series of events that involve the activation of T lymphocytes and the elimination of pathogens.

Figure: MHC presentation and virus infected cells

The host immune system activates cell-mediated immunity after exposure to intracellular pathogens or when the body tries to combat altered self cells (tumor cells). CMI has the property of specificity and diversity, memory, specialization, self-limitation, and non-reactivity to self.

Cells Involved in Cell-Mediated Immunity (CMI)

Both antigen-specific and non-specific cells are involved in CMI. Antigen-specific cells are T cells, whereas non-specific cells are macrophages, neutrophils, and natural killer cells.

Figure: Simplified overview of the processes involved in the primary immune response

Primary Immune Response

The chief components of CMI are:

T cell

T cells are essential in the immune system’s surveillance for cancer, responsible for most autoimmune diseases, and rejection of organ transplants. T cells are produced in the bone marrow and mature in the thymus.

T cells undergo positive and negative selection processes in the thymus:

1. Positive selection for thymocytes bearing TCR capable of binding self-MHC molecules results in MHC restriction.
2. Negative selection eliminates thymocytes bearing high-affinity receptors for self-MHC molecules alone or self-antigen presented by self-MHC, which results in self-tolerance.

Figure: MHC restriction and clonal selection

Cells reacting to self-antigens are killed by a programmed cell death called apoptosis. On the other hand, selected T cells undergo rapid expansion of clones of antigen-specific T lymphocytes producing a distinct sub-population of mature T cells.

Types of T-Cell (sub-population)

Figure: T Cell Types

1. Helper T cell (TH): TH cells are also called CD4+ cells, as these cells bear CD4 receptors. Helper T cell lies at the center of adaptive immunity, which coordinates with all other immune mechanisms. It relates to cytotoxic T cells via cytokines, humoral immunity via B cells, and innate immunity via neutrophils and macrophages. TH cells recognize target cells by interaction of CD4 receptor with MHC II molecules on the cell surface of the target cell.

2. Cytotoxic T cell: CD8+ cells or cytotoxic T cells (Tc) bear CD8 receptors. These are the main actor of cellular immunity. Tc releases toxin and directly kill pathogens or cancerous host cells. These cells recognize antigens on the surface of virus-infected cells, tumor cells, and allograft cells with a surface molecule, MHC I, and destroy target cells.

3. Regulatory/Suppressor T cell: If the immune system is not needed, these types of cells down-regulate the proliferation of effector T cells. Such cells also distinguish between self and non-self antigens.

How cytotoxic T cells kill

A cytotoxic (CD8) T cell that recognizes a target cell kills it by two main mechanisms:

The perforin-granzyme pathway. The T cell releases perforin, which forms pores in the target cell membrane, and granzymes, which enter through those pores. Granzymes are enzymes that trigger apoptosis, programmed cell death, from within. This is the major killing mechanism.

The Fas-FasL pathway. The activated T cell displays Fas ligand (FasL), which binds Fas on the target cell. This binding also triggers apoptosis. It is a second, contact-dependent route to the same outcome.

In both pathways the target cell is driven to kill itself by apoptosis rather than being burst open, which contains the infection neatly without spilling viral contents. Cytotoxic T cells can also release cytokines such as interferon-gamma that make nearby cells more resistant to infection.

Delayed-type hypersensitivity is a separate effector function, driven mainly by CD4 Th1 cells that activate macrophages. It underlies the tuberculin skin test and contact dermatitis (such as poison ivy), and is covered in detail in the article on type IV hypersensitivity.

Regulatory Functions of T Cells

Regulation of antibody production Stimulation of helper and cytotoxic T cells to participate in the CMI Suppression of specific immune responses.

MHC restriction: how T cells see antigen

Figure: MHC and presentation

T cells recognize antigen only when it is displayed on an MHC molecule, a rule called MHC restriction. CD8 cytotoxic T cells read MHC class I (present on all nucleated cells), and CD4 helper T cells read MHC class II (present only on antigen-presenting cells).

How MHC molecules present antigen, and the "rule of eight" memory device for this pairing, is covered in a separate article on MHC molecules. For cell-mediated immunity, the key point is that MHC class I lets a cytotoxic T cell inspect what is happening inside any body cell, which is exactly how it catches a virus-infected or tumor cell.

Figure: MHC restriction

The T-cell receptor recognizes a specific antigen only when that antigen is bound to an MHC molecule, never as a free protein. Most T-cell receptors are made of an alpha and a beta chain, and gene rearrangement gives each T cell a unique receptor, which is the source of the enormous diversity of T-cell specificities.

Cytokines

Cytokines are the chemicals released by T cells for communication and response to kill cells carrying pathogens. These are signaling proteins and glycoproteins which can turn on or off the immune response. CMI stimulates cells to secrete cytokines that signal various cells of adaptive and innate responses. Interleukins, interferons, and growth factors are examples of cytokines. Both antigen-specific and non-specific cells of CMI require cytokines.

Additional Components

Macrophages and dendritic cells phagocytize microbes and present antigens to T cells. Natural killer (NK) cells detect and kill infected cells using innate receptors.

Mechanism of Cell-Mediated Immunity (CMI)

CMI requires direct cell-to-cell contact or acts by chemical stimulation of cytokines to respond to intracellular antigens. The mechanism of CMI can be better understood with the help of the following steps:

Recognition of foreign antigens

Numerous T lymphocytes can recognize and respond to a distinct antigenic determinant. And when an antigen enters, it selects a specific preexisting clone and activates it, called clonal selection.

Activation of T lymphocytes

An antigen-presenting cell displays a processed antigen fragment, and a helper T cell that recognizes it becomes activated. The activated helper T cell then coordinates the wider response: it proliferates into subsets such as Th1 and Th2, and its cytokines activate cytotoxic T cells and macrophages (Th1) or help B cells make antibody (Th2).

The detailed two-signal mechanism of how a T cell is activated is covered in a separate article on T lymphocyte activation. What matters here is what the activated cells then do.

Figure: Effector mechanism of cell mediated immunity

Antigen elimination by effector mechanism

In effector phage, pathogens are eliminated, and memory cells are formed. Activated Tc proliferates and differentiates into a mature Tc, which binds to an infected target cell and initiates the destruction of that cell. MHC I of infected cell surface binds with CD8 receptors of Tc. Then it secretes perforin, granzymes protein, and lymphatic toxins for viruses or intracellular bacteria, or carcinogenic cells.

Activated Tc proliferates to form a clone of cells, each with TCR with the same antigen determinant. Effector cells directly encounter and eliminate other infected cells. The effector mechanism induces apoptosis in cells displaying epitopes of foreign antigens on their surface.

Cytotoxin secretion, leukocyte activation, cell-mediated cytotoxic responses, and hypersensitivity type IV are the parts of the effector mechanism. Similarly, activated macrophages and NK cells destroy intracellular pathogens.

Return to homeostasis

After eliminating antigens, the immune system returns to its basal resting state. It is because most of the progeny of antigen-stimulated lymphocytes die by apoptosis. So such lymphocytes need to come to the previous state at the end of the immune response.

Maintenance of memory

When the antigen first primes the naïve T cells, a primary immune response occurs in which clonal expansion of T- cell occurs. These cells outnumber many of the other T-cell clones in circulation. After the infection has resolved, many of the antigen-specific T cells die by apoptosis, and the remaining few persist as memory cells.

These cells, called memory T cells, confer the ability to respond rapidly and vigorously for many years for the same antigen (pathogen). Memory cells live for many years and can reproduce themselves over many cell generations. On subsequent exposure to the antigen, these few T-cell clones rapidly proliferate again as part of a secondary immune response.

The surface protein they express makes them different from naïve and recently activated effector cells. Memory T cells express higher levels of adhesion molecules than naïve T cells, such as integrins and CD44, which enhance the migration of the memory cells to sites of infection anywhere in the body. If the antigen reenters the body, it can rapidly activate, proliferate, and differentiate into effector cells to eliminate the antigen. Memory cells circulate in the blood (effector T memory) or are found in tissues (resident T memory).

Importance of Cell-Mediated Immunity (CMI)

• CMI plays an efficient role in killing intracellular pathogens and altered-self cells. It destroys virus-infected cells, intracellular bacteria, and cancer cells. It also kills dysfunctional cells by inducing apoptosis.
• T cells regulate the proliferation and activity of other immune system cells like B cells, macrophages, neutrophils, etc.
• Regulatory T cells provide immune tolerance for commensal organisms, graft/ transplant, pregnancy, or tumors.

Functions of Cell-Mediated Immunity

1. Cell-mediated immunity protects the host against several intracellular bacteria (such as Mycobacterium tuberculosis, atypical mycobacteria, Legionella pneumophila, and Listeria monocytogenes), fungi, and parasites. The cell-mediated immune response is involved in granuloma formation.  Granuloma formation is seen in major systemic fungal diseases such as coccidiodomycosis, histoplasmosis, and blastomycosis.
2. Cell-mediated immunity kills virus-infected cells and altered self-cells (tumor cells). Cytotoxic T cells are responsible for killing virus-infected cells.
3. Graft and tumor rejection
4. Regulation of antibody response (help and suppression)
5. Allergy (hypersensitivity). For example, poison oak

Reduced cell-mediated immunity predisposes people to infections with the following pathogens;

1. Nocardia asteroides
2. Mycobacterium leprae(in people with lepromatous leprosy, the cell-mediated response to M. leprae is defective)
3. Herpes simplex virus (HSV): Suppressing cell-mediated immunity often results in reactivation, spread, and severe infections with HSV.
4. Varicella-zoster virus (VZV): Suppression of cell-mediated immunity reactivates the VZV latently residing in infected cells and causes zoster (shingles).
5. Cytomegalovirus: Suppression of cell-mediated immunity can cause systemic infections with cytomegalovirus.
6. Epstein-Barr virus (EBV): Reduced cell-mediated immunity predisposes to the uncontrolled growth of the EBV-infected cells.
7. Fungal infections: Suppression of cell-mediated immune response can lead to reactivation and dissemination of asymptomatic fungal infections and opportunistic fungal infections. For example, a disease caused by Cryptococcus neoformans occurs mainly in patients with reduced cell-mediated immunity, especially AIDS patients. Reduced cell-mediated immunity also predisposes to disseminated disease caused by systemic fungi, such as Histoplasma and Coccidioides.
8. Toxoplasma gondii: In patients with reduced cell-mediated immunity (e.g., patients with AIDS), life-threatening toxoplasmosis, primarily encephalitis can occur. Cell-mediated immunity is responsible to limit the spread of tachyzoites of T. gondii.

Dysfunction of CMI

• Type IV (delayed) hypersensitivity, along with tissue and transplant rejection, is driven by cell-mediated immunity. Type IV hypersensitivity is covered in its own article.
• Superantigens bypass normal antigen processing to activate a huge fraction of T cells at once, causing a damaging cytokine flood. This is covered in a separate article on superantigens.
• CMI may induce autoimmune disorders (diabetes, multiple sclerosis, rheumatoid arthritis).
• CMI can cause an allergic condition like gluten intolerance.

How to remember

CMI = the inside job. Humoral immunity handles threats outside cells (in blood and fluids); cell-mediated immunity handles threats inside cells (viruses, intracellular bacteria, tumors). If the enemy is hiding inside a cell, it is a CMI problem.

Two ways a killer T cell kills: "poke and provoke." Poke: perforin makes pores, granzymes enter and trigger apoptosis. Provoke: Fas ligand binds Fas and triggers apoptosis. Both end in the target killing itself.

The deficiency tells the story. What CMI does is easiest to remember by what happens when it fails: reactivated herpes and shingles, disseminated TB and fungi, Toxoplasma encephalitis. These are the "inside-the-cell" infections that CMI normally holds in check.

Th1 for cells, Th2 for antibody. Th1 cytokines arm cytotoxic T cells and macrophages (cell-mediated); Th2 cytokines help B cells make antibody (humoral). The helper T cell chooses which arm to strengthen.

Key exam facts in one table

Where students get confused

"Cell-mediated immunity means no antibodies are involved." Correct in emphasis but not absolute. CMI is the T-cell and cytotoxic arm, focused on intracellular threats. But helper T cells (part of CMI) also help B cells make antibody, so the two arms are linked, not walled off.

"Cytotoxic T cells kill by bursting the cell open." No. They drive the target cell to kill itself by apoptosis, using perforin/granzyme or Fas-FasL. Apoptosis contains the infection; bursting (necrosis) would spill it.

"Cell-mediated immunity is only about killing." No. It also includes delayed hypersensitivity, macrophage activation, granuloma formation, and regulation of other immune cells. Killing is the headline, not the whole job.

"CMI and humoral immunity are completely separate systems." No. The helper T cell sits at the junction: Th1 strengthens cell-mediated responses, Th2 strengthens antibody responses. One cell type coordinates both arms.

"If cell-mediated immunity fails, you just get more colds." No, the pattern is specific. CMI failure reactivates intracellular infections: shingles, TB, CMV, Toxoplasma. This predictable list is a fingerprint of CMI deficiency, seen classically in AIDS.

References

• Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 10th ed. Elsevier; 2022.
• Punt J, Stranford SA, Jones PP, Owen JA. Kuby Immunology. 8th ed. W.H. Freeman; 2019.
• Levinson W, Chin-Hong P, Joyce EA, et al. Review of Medical Microbiology and Immunology. 17th ed. McGraw Hill; 2022.