Cell-Mediated Immunity (CMI): T Cell Types and Functions

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.

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.

CI (Cell-Mediated Immunity)
Simplified overview of the processes involved in the primary immune response Image Source: 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.
MHC Restriction and Clonal Expansion
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)

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.
  1. 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.
  1. 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.

Functions of T Cells

  1. Effector Functions of T Cells
    1. Cytotoxicity
      • By inserting perforins and granzymes (degrading enzymes) into the infected cell,
      • By the Fas–Fas ligand (FasL) interaction, and
      • By antibody-dependent cellular cytotoxicity (ADCC) mechanism.
    2. Delayed hypersensitivity
  2. Regulatory Functions of T Cells
    1. Regulation of antibody production
    2. Stimulation of helper and cytotoxic T cells to participate in the CMI
    3. Suppression of specific immune responses.

MHC and Antigen Presenting cells

MHC  and presentation

All the nucleated cells except sperm cells and neurons bear major histocompatibility complex (MHC) molecules on the surface. MHC is classified as class I and class II. All the nucleated cells bear MHC class I, whereas professional antigen-presenting cells (APCs) have MHC I and MHC II on their surfaces.

T cells recognize only polypeptide antigens when they are presented in association with MHC proteins.
Remember the “rule of eight”: CD4-positive T cells recognize antigen in association with class II MHC proteins (4 × 2 = 8), whereas CD8-positive T cells recognize antigen in association with class I MHC proteins (8 × 1 = 8). This is called MHC restriction because each type of T cell is “restricted” to recognize antigen only when presented by the appropriate class of MHC protein.

MHC restriction

MHC restriction is a feature of thymic positive selection. It is mediated by specific binding sites on the TCR as well as on the CD4 and CD8 proteins that bind to specific regions on the MHC proteins.

T-cell Receptor

T cell is characterized by TCR on the surface. TCR recognizes specific antigens presented by APC. Each T lymphocyte is genetically programmed to produce TCR, through a series of gene translocations, having a unique shape to fit a specific epitope. Rearrangement of TCR genes and expression of various membrane markers makes T cell-specific and diverse. Most TCRs consist of an alpha and a beta chain. TCR only reacts with MHC-bound antigens; TCR can react with complementary shaped peptides bound to an MHC molecule.

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

Activation of T lymphocytes requires exposure to microorganisms. Innate immunity also enhances the activation of T lymphocytes.

When a macrophage captures, engulfs, and digests an antigen, it presents an antigen fragment on its surface. Interactions between proteins on the macrophage and helper T cell occur, activating the helper T cell.

Activated TH cells secrete cytokines and activate cytotoxic T cells, B cells, macrophages, and natural killer (NK) cells.

T helper cell proliferates into either TH1 or TH 2 cells, which secrete different types of cytokines. Interaction between the TH2 and B cells causes proliferation, differentiation, and production of antibodies. Cytokines secreted by the TH1 cell activate cytotoxic T cells and macrophages.

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

  • Hypersensitivity type IV, tissue, and transplant rejections occur because of CMI.
  • Super antigens induce T cell activation by binding TCR and MHC simultaneously, and cytokines releases in a huge amount, adversely affecting the host.
  • CMI may induce autoimmune disorders (diabetes, multiple sclerosis, rheumatoid arthritis).
  • CMI can cause an allergic condition like gluten intolerance.

References

Srijana Khanal

Hello, I am Srijana Khanal. Former faculty teacher in Microbiology Department at National College, NIST. Involved in the field of teaching for almost 10 years. I am very passionate about writing (academic as well as creative). My areas of interest are basic science, immunology, genetics, and research methodology.

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