Cell Mediated Immune Response – Definition, Mechanism, Cells Involved

Cell mediated immune response is a type of adaptive immune response in which T lymphocytes directly react against the foreign antigen. It does not mainly depend on circulating antibody. It is mostly active against intracellular pathogens, infected cells and some abnormal cells.

This immune response is mainly carried out by cytotoxic T cells (CD8⁺) and T helper 1 cells (Th1 or CD4⁺). Cytotoxic T cells recognize antigen present on the surface of infected host cell. Then it kills the target cell before the pathogen multiply more inside the cell.

Th1 cells are important for the defense against pathogens which can live inside macrophages. Examples include bacteria causing tuberculosis and leprosy. When Th1 cells recognize the specific antigen, they release cytokines like interferon-gamma (IFN-γ) and activate the infected macrophage by direct cell to cell contact through CD40.

After activation, macrophages increase their killing activity. They produce reactive oxygen species and reactive nitrogen species such as nitric oxide (NO). These substances help to digest and destroy the engulfed microorganism present inside the macrophage.

In some condition, if the activated macrophage cannot remove the pathogen, Th1 cells may induce apoptosis of that macrophage. This is programmed cell death. By this process the protective place of pathogen is removed and the infection is controlled.

Thus, cell mediated immune response is mainly concerned with killing of infected cells and activation of macrophages. It is very important in protection against viruses, intracellular bacteria and other pathogens which cannot be removed properly by antibody mediated response.

Definition of Cell Mediated Immune Response 

Cell-mediated immunity is a type of adaptive immunity in which T lymphocytes directly act against infected or abnormal body cells. It does not mainly depend on antibody. It is important against intracellular pathogens like viruses and some bacteria.

Characteristics of Cell Mediated Immune Response

• Cell mediated immune response mainly gives protection against intracellular pathogens. It acts against viruses, mycobacteria and tumor cells. It is not mainly dependent on circulating antibodies.
• This response is carried out by T lymphocytes. The main cells involved are CD4⁺ T helper 1 (Th1) cells and CD8⁺ cytotoxic T cells.
• T cells recognize antigen only when it is presented with Major Histocompatibility Complex (MHC) molecules. The antigen is first processed into small peptide fragments. Then it is shown on the surface of antigen presenting cells or infected host cells.
• Activation of naive T cells needs three signals. First is antigen recognition. Second is co-stimulation such as CD28 binding with B7-1/B7-2 on antigen presenting cell. Third is cytokine signal which helps in differentiation of the T cell.
• CD8⁺ cytotoxic T cells directly kill the infected target cells. It also destroys tumor cells in antigen specific manner. This removes the site where pathogen multiply inside the cell.
• Th1 cells activate macrophages by secreting cytokines like interferon-gamma (IFN-γ). They also use direct cell to cell contact through CD40 ligand. Activated macrophages then kill ingested microbes by producing reactive oxygen and nitrogen species.
• This response also forms memory T cells after the infection is cleared. These memory cells remain for long time. They give rapid and specific protection when the same pathogen enters again.

Importance of Cell Mediated Immunity

• Cell mediated immunity is important for protection against intracellular pathogens. It fights against viruses and some bacteria like Mycobacterium tuberculosis and Mycobacterium leprae. These microbes can survive and multiply inside the host cells.
• It helps in destruction of infected host cells. CD8⁺ cytotoxic T cells directly recognize the infected cells and kill them. This removes the place where pathogen is protected and multiplying.
• Cell mediated immunity is important in tumor immunosurveillance. It recognizes abnormal tumor cells and cancer cells. Then these cells are destroyed by the immune response.
• It activates macrophages for killing of ingested pathogens. Th1 CD4⁺ T cells release cytokines mainly interferon-gamma (IFN-γ). This increases the microbicidal activity of macrophages and helps them to destroy resistant microbes.
• It coordinates the immune system by release of cytokines. T cells regulate and attract other white blood cells like B cells, neutrophils and natural killer (NK) cells. So the immune response become more effective.
• It gives long-term immunological memory. After the infection is cleared, some memory T cells remain in the body. Tissue-resident memory T cells (Trm) stay in barrier tissues and give rapid protection when same pathogen enters again.
• It helps in granuloma formation when the pathogen cannot be completely removed. A localized inflammatory structure called granuloma is formed around the pathogen. This walls off the infection and prevents spreading in the body.

Cells Involved in Cell Mediated Immune Response

• T Cells
  T lymphocytes (T cells) are the main cells of cell mediated immune response. These cells recognize foreign antigen and produce the effector response. They do not mainly act by antibody formation.
• Th1 Cells
  CD4⁺ helper T cells mainly Th1 cells are the coordinating cells. They recognize antigen presented by antigen presenting cells. They release interferon-gamma (IFN-γ) and activate macrophages.
• Cytotoxic T Cells
  CD8⁺ cytotoxic T cells are the killing cells. They recognize infected host cells and tumor cells. Then they destroy these cells which contain intracellular pathogens like viruses.
• Memory T Cells
  Memory T cells are formed after infection is cleared. These cells remain in the body for long time. They give rapid and specific response when same pathogen enters again.
• Regulatory T Cells
  Regulatory T cells (Tregs) control the immune response. They suppress the reaction after infection is controlled. This prevents excessive inflammation and autoimmune damage.
• APCs
  Antigen presenting cells (APCs) are needed for activation of naive T cells. They capture the antigen, process it and present it on their surface. This starts the cell mediated response.
• Dendritic Cells
  Dendritic cells (DCs) are the most efficient APCs. They collect antigen from infection site. Then they migrate to lymph nodes and present antigen to T cells.
• Macrophages
  Macrophages are phagocytic cells and also act as APCs. They present antigen to T cells. After activation by Th1 cells, they destroy ingested intracellular pathogens.
• B Cells
  B lymphocytes are mainly cells of humoral immune response. But they also work as APCs. They process protein antigen and present it to helper T cells.
• NK Cells
  Natural killer (NK) cells are large granular lymphocytes. They give early nonspecific defense. They kill virus infected cells and tumor cells.
• Inflammatory Cells
  Neutrophils, mast cells and epithelial cells are supporting cells at the inflammatory site. They release cytokines and chemokines. These substances recruit macrophages and increase the T cell response.

Role of T Cells in Cell Mediated Immune Response

• Antigen Recognition
  Naive T cells continuously move through peripheral lymphoid organs. They recognize specific foreign antigen presented by MHC molecules on antigen presenting cells. After recognition they become activated effector T cells.
• T Cell Activation
  Activation of T cells takes place when antigen is properly presented. The cells then increase in number and differentiate into active cells. These activated cells take part in killing and coordination of immune response.
• Macrophage Activation
  CD4⁺ Th1 cells are the main coordinating cells of cell mediated immunity. They secrete interferon-gamma (IFN-γ) and also use CD40-CD40L contact. This highly activates infected macrophages and increases their microbicidal power.
• Apoptosis Induction
  If macrophage cannot remove the intracellular pathogen, Th1 cells can bind with that macrophage. Then they induce apoptosis or programmed cell death. This removes the protective place where pathogen was surviving.
• Cell Recruitment
  Activated Th1 cells release cytokines and chemokines. These include TNF-α and TNF-β. They recruit fresh phagocytic cells like macrophages and neutrophils from blood to the site of infection.
• Direct Killing
  CD8⁺ cytotoxic T cells directly bind with infected host cells. They kill virus infected cells and tumor cells in antigen specific manner. This helps to remove the pathogen before it multiply more.
• Memory Formation
  After infection is cleared, some effector T cells become memory T cells. These cells remain for long time in the body. They give faster and stronger response when same pathogen enters again.
• Transplant Rejection
  T cells also take part in transplant rejection. They recognize foreign MHC molecules on donor tissue or processed donor peptides. This can cause acute and chronic graft rejection.

Mechanism of Cell Mediated Immune Response

1. Antigen Processing
   In this step, antigen presenting cells (APCs) capture the foreign pathogen. Mainly dendritic cells take the antigen and break it into small peptide fragments. These fragments are then placed on the surface with MHC molecules.
2. Antigen Recognition
   Naive T cells recognize the antigen with the help of T cell receptor (TCR). The TCR binds with antigen-MHC complex present on the APC. This binding is supported by CD4 co-receptor in helper T cells and CD8 co-receptor in cytotoxic T cells.
3. Co-stimulation
   In this step, the T cell needs second signal for complete activation. CD28 receptor present on T cell binds with B7-1 (CD80) or B7-2 (CD86) present on APC. If this signal is absent, the T cell may become inactive or anergic.
4. Cytokine Signal
   The activated T cell receives cytokine signal from the surrounding area. These cytokines decide the type of differentiation. For example, IL-12 and interferon-gamma (IFN-γ) help naive CD4⁺ T cells to become Th1 effector cells.
5. T Cell Differentiation
   After receiving all signals, the T cells divide and differentiate into armed effector cells. CD4⁺ T cells mainly form Th1 cells. CD8⁺ T cells form cytotoxic T cells which can kill infected cells.
6. Migration to Infection Site
   The activated effector T cells move from lymphoid organs to the site of infection. They reach the infected tissue where antigen is present. Then they perform their immune function.
7. Macrophage Activation
   Th1 cells activate infected macrophages. They secrete interferon-gamma (IFN-γ) and also make contact through CD40-CD40L molecules. This activates macrophages strongly and increases its killing power.
8. Pathogen Destruction
   Activated macrophages produce reactive oxygen species (ROS) and nitric oxide (NO). These substances digest and destroy the engulfed intracellular pathogens. This is important for microbes living inside macrophages.
9. Direct Cytotoxicity
   CD8⁺ cytotoxic T cells recognize infected target cells. They bind with antigen presented on the target cell surface. Then they kill the infected cell and remove the place where pathogen multiply.
10. Apoptosis
    If the activated macrophage cannot destroy the pathogen, Th1 cells can induce apoptosis. They bind with Fas receptor through Fas ligand (FasL). This causes programmed cell death of macrophage and removes the pathogen hiding site.

Cytokines Involved in Cell Mediated Immune Response

1. IFN-γ
   Interferon-gamma (IFN-γ) is the most important cytokine in cell mediated immune response. It is released from Th1 cells and CD8⁺ T cells. It activates macrophages and helps to stop multiplication of intracellular pathogens.
2. IL-12
   Interleukin-12 (IL-12) is produced by activated antigen presenting cells. Mainly dendritic cells produce it. It helps the naive CD4⁺ T cells to change into Th1 cells.
3. TNF-α
   Tumor necrosis factor-alpha (TNF-α) acts along with IFN-γ. It helps in activation of macrophages. It also helps in apoptosis of infected cells and formation of granuloma.
4. IL-2
   Interleukin-2 (IL-2) is a growth factor for T cells. It helps in multiplication and survival of T cells. It also activates natural killer (NK) cells.
5. IL-7 and IL-15
   Interleukin-7 (IL-7) and interleukin-15 (IL-15) are survival cytokines. They maintain memory CD8⁺ T cells for long time. These cytokines also help in survival of tissue resident memory T cells.
6. IL-17
   Interleukin-17 (IL-17) is released by Th17 cells. It attracts neutrophils at the site of infection. It is mainly useful against extracellular bacteria and fungi.
7. TGF-β
   Transforming growth factor-beta (TGF-β) helps in formation of tissue resident memory T cells (Trm). These cells remain in tissues like skin and gut. It helps to keep these cells in barrier tissues.
8. GM-CSF
   Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases macrophage activity. It also helps in production of IFN-γ producing T cells. So it supports the cell mediated immune reaction.
9. IL-10
   Interleukin-10 (IL-10) is an inhibitory cytokine. It reduces macrophage activity and controls the immune response. It prevents too much tissue damage, but some pathogens like Mycobacterium leprae may use it for their survival.

Difference Between Cell Mediated and Humoral Immune Response

• Main cell
  Cell mediated immune response is the immune response where T lymphocytes are mainly involved.
  Humoral immune response is the immune response where B lymphocytes are mainly involved.
• Helper cell
  In cell mediated immunity, the helper cell is mainly Th1 cell.
  In humoral immunity, the helper cell is mainly Th2 cell.
• Target antigen
  Cell mediated immunity acts against the antigen which is present inside the body cell.
  Humoral immunity acts against the antigen which is present outside the cell in body fluid.
• Pathogen type
  Cell mediated immunity is important for viruses and intracellular bacteria like Mycobacterium tuberculosis.
  Humoral immunity is important for extracellular bacteria and toxins.
• Mode of action
  In cell mediated immunity, activated T cells destroy the infected cell.
  Some T cells also activate macrophage for killing of ingested microbes.
  In humoral immunity, B cells change into plasma cells and produce antibody.
• Antigen recognition
  In cell mediated immunity, T cell recognize antigen only with MHC molecule.
  In humoral immunity, B cell and antibody bind with intact antigen directly.
• Main product
  The main product of cell mediated immunity is activated T cells and cytokines.
  The main product of humoral immunity is antibody.
• Site of action
  Cell mediated immunity acts mainly in infected tissue and infected cell.
  Humoral immunity acts mainly in blood, lymph and other body fluid.
• Example
  Cell mediated immunity is seen in viral infection, tuberculosis and tumor cell destruction.
  Humoral immunity is seen in bacterial toxin neutralization and extracellular bacterial infection.

Cell Mediated Immune Response Against Intracellular Pathogens

• Intracellular pathogens are those microorganisms which enter inside the host cell and multiply there. These include viruses and some bacteria like Mycobacterium tuberculosis. As they remain inside the host cell, circulating antibody cannot reach them properly, so cell mediated immune response is needed for their destruction.
• The defense against intracellular pathogen is mainly carried out by T lymphocytes. The important cells are CD4⁺ Th1 cells and CD8⁺ cytotoxic T cells. These cells either activate the infected macrophage or directly destroy the infected host cell.
• Some bacteria can survive inside the vesicles of macrophage after phagocytosis. They resist the normal killing mechanism of macrophage and remain protected inside it. In this condition, macrophage alone is not able to digest the pathogen properly.
• Th1 cells activate the infected macrophage by giving two important signals. One is secretion of interferon-gamma (IFN-γ) and another is direct contact through CD40-CD40L molecules. These two signals make the macrophage strongly activated and increase its microbicidal activity.
• After activation, macrophage changes its internal killing system. The phagosome fuses with lysosome and toxic substances are produced inside it. Reactive oxygen species (ROS) and nitric oxide (NO) are formed, which help in digestion and destruction of engulfed intracellular pathogen.
• Some intracellular pathogens escape from vesicle and enter into the cytoplasm of infected cell. In this condition, macrophage killing system cannot remove them properly. CD8⁺ cytotoxic T cells recognize such infected cells and destroy them directly, so the place of pathogen multiplication is removed.
• When the infected cell is killed by CD8⁺ T cell, the hidden pathogen may be released outside the cell. Then these pathogens are taken up by fresh activated macrophages. In this way the pathogen is again exposed to killing by phagocytic cells.
• If the infected macrophage cannot kill the pathogen even after activation, Th1 cells may induce apoptosis of that macrophage. This is done by binding of Fas ligand (FasL) with Fas receptor on macrophage. This programmed cell death removes the protective site where the pathogen was surviving.
• When the pathogen cannot be completely destroyed, the immune system forms a localized inflammatory structure called granuloma. It is made up of activated macrophages, fused macrophages and lymphocytes around the infected area. This structure walls off the pathogen and prevents spread of infection in the body.
• After the infection is controlled, some memory T cells remain in the body. Tissue resident memory T cells (Trm) may stay in tissues like lung, skin and gut. When same pathogen enters again, these cells rapidly release IFN-γ and TNF-α and start early protection.

Role of Cell Mediated Immunity in Transplant Rejection

• Cell mediated immunity plays a major role in transplant rejection. The transplanted tissue is genetically different from the recipient body. So the recipient immune system identify the transplanted organ as foreign tissue or alloantigen.
• The rejection response is mainly produced by T lymphocytes. These T cells recognize the foreign MHC molecules and other donor antigens present in the graft. After this recognition, the T cells become activated and start immune reaction against the transplanted tissue.
• In direct allorecognition, donor antigen presenting cells are present in the transplanted organ. These cells are also called passenger APCs, mainly dendritic cells. They migrate to the recipient lymph node and present intact foreign MHC molecules directly to recipient T cells.
• This direct recognition activates large number of recipient T cells. The activated T cells then attack the graft rapidly. This is important in acute rejection, where the transplanted organ is damaged in short time due to strong cellular immune response.
• In indirect allorecognition, the recipient APCs take up the dead donor cell proteins from the transplanted organ. These proteins are processed into small peptides. Then they are presented with recipient MHC molecules to recipient T cells.
• This indirect pathway produces a slow and continuous immune response. It is mainly responsible for chronic rejection. In this process, the graft becomes gradually scarred, blood vessels become damaged and the transplanted organ slowly loses its function.
• In semi-direct allorecognition, recipient APCs acquire intact donor MHC molecules from donor cells. These donor molecules may be taken by cell contact or extracellular vesicles. Then recipient APCs show these foreign MHC molecules on their own surface and activate T cells.
• CD8⁺ cytotoxic T cells act as the main killing cells in transplant rejection. They migrate to the transplanted tissue and bind with graft cells. Then they directly kill the graft cells and damage the transplanted organ.
• CD4⁺ helper T cells coordinate the rejection response. They release cytokines and activate other immune cells. They also help B cells to produce antibody against graft antigen, mainly during long term antibody mediated rejection.
• The cytokines released by activated T cells attract macrophages and other inflammatory cells into the graft. These cells produce inflammation inside the transplanted tissue. This increases tissue injury and vascular damage of the graft.
• In bone marrow transplantation, the reaction may occur in reverse direction. This is called graft-versus-host disease (GVHD). In this condition, donor T cells present in the graft recognize recipient tissues like skin, gut and liver as foreign and attack them.
• Thus, cell mediated immunity is very important in transplant rejection. It recognizes foreign donor antigen, activates T cells, kills graft cells and produces inflammation. This finally causes rejection of transplanted tissue if immune response is not controlled.

Role of Cell Mediated Immunity in Delayed Hypersensitivity

• Delayed hypersensitivity is a type of cell mediated immune reaction. It is mainly controlled by CD4⁺ Th1 cells and macrophages. Antibody is not the main factor in this reaction.
• This reaction starts when the antigen enters the tissue again and is recognized by antigen specific Th1 cells. These T cells move to the local site where antigen is present. Then the delayed reaction is produced slowly, usually after some time.
• After antigen recognition, activated Th1 cells release interferon-gamma (IFN-γ) and other lymphokines. These substances attract monocytes, macrophages and other lymphocytes at the site. So a local inflammatory reaction is produced.
• IFN-γ activates macrophages strongly. Activated macrophages become more phagocytic and microbicidal. They produce toxic substances which help in killing of intracellular microbes.
• This reaction is important against intracellular bacteria like Mycobacterium tuberculosis and Mycobacterium leprae. These bacteria can live inside macrophage phagolysosome. So cell mediated immunity is required for their destruction.
• In chronic infection, the antigen may remain for long time. Then more macrophages and T cells collect at the site. This forms a localized structure called granuloma.
• Granuloma is formed by activated macrophages, fused macrophages and lymphocytes around the antigen. It helps to wall off the antigen and prevent spreading. But it may also damage the surrounding normal tissue.
• In delayed hypersensitivity, tissue injury occurs due to excessive activation of macrophages and T cells. The inflammatory mediators destroy infected cells but also injure nearby host cells. So the reaction is protective and harmful both.
• In transplant rejection, delayed type reaction is also important. Recipient cells process donor antigen and present it to recipient T cells. This indirect recognition slowly produces inflammation and chronic vascular rejection of the graft.
• Thus, cell mediated immunity in delayed hypersensitivity works by activation of Th1 cells, release of cytokines and activation of macrophages. It is useful for intracellular pathogen, but prolonged reaction may cause granuloma formation and tissue damage.

Disorders Related to Cell Mediated Immune Response

1. Autoimmune disease
   Autoimmune disease occurs when self tolerance is lost. In this condition self reactive T cells attack the body’s own tissues. Examples are vitiligo, multiple sclerosis, rheumatoid arthritis, psoriasis, alopecia areata, type I diabetes mellitus, autoimmune hepatitis and myasthenia gravis.
2. SCID
   Severe combined immunodeficiency (SCID) is a genetic immunodeficiency disease. In this disease T lymphocytes are very low in number or their function is reduced. So the patient becomes highly susceptible to opportunistic infections.
3. Hyper-IgM syndrome
   Hyper-IgM syndrome occurs due to defect in CD40 ligand on T cells. Due to this defect T cells cannot interact properly with B cells. So antibody class switching is not done normally.
4. Transplant rejection
   Transplant rejection occurs when graft tissue is recognized as foreign tissue. Recipient T cells become activated against the graft. It may cause acute rejection or chronic rejection of transplanted organ.
5. GVHD
   Graft-versus-host disease (GVHD) is mainly seen after bone marrow transplantation. Donor T cells present in the graft recognize recipient tissue as foreign. Then they attack skin, liver and gut.
6. T-cell lymphoma
   T-cell lymphoma is a cancer of T lymphocytes. It occurs due to abnormal growth of T cells. It may be related with genetic changes in T cell receptor, co-stimulatory pathway or cytokine receptor pathway.
7. Tuberculosis and leprosy
   In tuberculosis and leprosy, cell mediated immunity is needed for protection. But long continued reaction may damage tissue. In tuberculosis, delayed hypersensitivity may cause granuloma formation and caseation necrosis.
8. Pathologic inflammation
   Pathologic inflammation occurs when T cell response becomes excessive or uncontrolled. In lung, tissue resident memory T cells (Trm) may produce chronic inflammation. This may help in development of asthma and pulmonary fibrosis.

Biological and Clinical Significance of Cell Mediated Immune Response

• Hidden pathogen
  Cell mediated immune response is important for defense against hidden pathogens. These pathogens live and multiply inside the host cell. Examples are viruses, Mycobacterium tuberculosis and Mycobacterium leprae where antibody cannot reach properly.
• Macrophage activation
  CD4⁺ Th1 cells activate macrophages by releasing interferon-gamma (IFN-γ). After activation macrophage become more powerful for killing of ingested microbes. It produces reactive oxygen and nitrogen substances for destruction of pathogen.
• Granuloma
  When the pathogen is not completely destroyed, cell mediated immunity helps in formation of granuloma. It is a localized structure formed by macrophages and lymphocytes. It walls off the pathogen and stops spreading of infection.
• Cytotoxic action
  CD8⁺ cytotoxic T cells kill infected host cells directly. They also destroy tumor cells. This is important when pathogen is present inside cytoplasm or when abnormal cell is formed in body.
• Cross-presentation
  Cross-presentation is the process where dendritic cells present extracellular antigen to CD8⁺ T cells. This is important in viral immunity and tumor surveillance. By this process cytotoxic T cells become activated against infected or tumor cell.
• Memory response
  After infection is cleared, memory T cells remain in the body. Tissue resident memory T cells (Trm) stay in lung, skin and gut. They give quick response when same pathogen enters again.
• TB diagnosis
  The principle of cell mediated immunity is used in clinical diagnosis of tuberculosis. In Interferon-Gamma Release Assay (IGRA), T lymphocytes release IFN-γ after contact with specific TB antigen. This helps in detection of latent and active tuberculosis.
• Cancer therapy
  Cell mediated immunity is used in modern cancer treatment. In CAR T-cell therapy, patient T cells are modified to attack cancer cells. In checkpoint inhibitor therapy, blocking molecules like PD-1 and CTLA-4 are inhibited so that exhausted T cells can attack tumor cell again.
• Transplant rejection
  In transplanted organ, recipient T cells recognize donor tissue as foreign. This recognition may be direct, indirect or semi-direct. It causes acute rejection and chronic rejection of the graft.
• GVHD
  Graft-versus-host disease (GVHD) occurs after bone marrow transplantation. Donor T cells present in graft recognize recipient tissues as foreign. They attack skin, gut and liver and cause severe disease.
• Autoimmune disease
  When self tolerance is lost, abnormal cell mediated response may attack own tissue. Autoreactive T cells may cause diseases like vitiligo and cutaneous lupus erythematosus. Excessive T cell inflammation may also contribute to asthma and pulmonary fibrosis.
• Vaccine response
  Modern vaccine design also needs cell mediated immunity. T follicular helper cells (Tfh) help B cells to form specific and long lasting antibody. This is important in newer vaccines like mRNA vaccines and nanoparticle vaccines.
• Pregnancy tolerance
  In pregnancy, fetal tissue contains paternal antigen. Cell mediated recognition can detect these antigens. But instead of rejection, immune tolerance is produced and this helps in survival of fetus.

Regulation of Cell Mediated Immune Response

1. Tregs
   Regulatory T cells (Tregs) are special type of CD4⁺ T cells. These cells suppress the immune response after its need is over. They maintain self tolerance and prevent the self reactive T cells from attacking normal body tissues.
2. Checkpoints
   Immune checkpoints are inhibitory receptors present on activated T cells. These act as brake system of immune response. When infection is controlled, these receptors reduce T cell activity and prevent severe tissue damage.
   • CTLA-4
     CTLA-4 is an inhibitory receptor present on T cells. It competes with CD28 for binding with B7 molecules on antigen presenting cells. By this process, T cell activation and proliferation is reduced.
   • PD-1
     PD-1 is another important inhibitory receptor of T cells. When PD-1 binds with PD-L1, it gives off signal to the T cell. During chronic infection, this may produce T cell exhaustion, where T cells become weak and less active.
   • LAG-3
     LAG-3 is a receptor which is similar to CD4 in structure. It binds with MHC class II molecules. This binding helps to control excessive T cell activation.
3. Anergy
   Clonal anergy occurs when a naive T cell recognize its antigen but does not get proper co-stimulatory signal. Signal 1 is present but Signal 2 is absent. Then the T cell becomes functionally inactive for long time.
4. Deletion
   Negative selection occurs in thymus during early development of T cells. The developing T cells which bind strongly with self antigen are removed. These cells undergo apoptosis, so autoimmune reaction is prevented.
5. Cross regulation
   Other T cell subsets can also regulate the cell mediated immune response. Th2 cells produce cytokines like IL-4. This shifts the response toward humoral immunity and decreases Th1 mediated cellular response.
6. Cytokine control
   Cytokines also help in regulation of the response. Some cytokines activate T cells, while some cytokines suppress them. This balance is needed so that the response can kill pathogen but does not damage normal tissue too much.

Laboratory Tests for Cell Mediated Immunity

1. Interferon-gamma release assay (IGRA)
   Interferon-gamma release assay (IGRA) is a blood test for cell mediated immune response. Blood cells are taken and mixed with specific antigen of Mycobacterium tuberculosis. Sensitized T cells release interferon-gamma (IFN-γ) after antigen stimulation. This IFN-γ is then measured.
   • QuantiFERON-TB Gold Plus (QFT-Plus) is an ELISA test. Whole blood is used. The amount of IFN-γ released in the blood sample is detected.
   • T-SPOT.TB is an ELISPOT test. PBMCs are first separated from blood. The T cells producing IFN-γ appear as spot forming cells.
2. Tuberculin skin test (TST)
   Tuberculin skin test (TST) is a skin test for cell mediated immune sensitization. Purified protein derivative (PPD) is injected into the skin. Sensitized T cells react at the injected site. Cytokines are released and macrophages collect there. Induration and swelling are formed after some time.
   • TST has less specificity than IGRA. PPD may react with BCG vaccine and non-tuberculous mycobacteria. False positive result may occur.
3. Mixed lymphocyte reaction (MLR)
   Mixed lymphocyte reaction (MLR) is a test used in transplant immunology. Lymphocytes of two different persons are mixed together. Foreign tissue antigen is recognized by T cells. Then T cells become activated and show proliferation.
   • It is used to study T cell reaction against graft antigen. It also shows possibility of cell mediated graft rejection.

References

1. Ahmadivand, S., Fux, R., & Palić, D. (2025). Role of T follicular helper cells in viral infections and vaccine design. Cells, 14(7), 508. https://doi.org/10.3390/cells14070508
2. AID Diagnostika. (n.d.). AID TB EliSpot assay – Diagnosis of latent & acute TB.
3. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Lymphocytes and the cellular basis of adaptive immunity. In Molecular biology of the cell (4th ed.). Garland Science.
4. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). The adaptive immune system. In Molecular biology of the cell (4th ed.). Garland Science.
5. American Cancer Society. (2025, December 15). Immune checkpoint inhibitors and their side effects.
6. A three signal model of T-cell lymphoma pathogenesis. (n.d.). PubMed Central (PMC).
7. Benichou, G., & Thomson, A. W. (2009). Direct versus indirect allorecognition pathways: On the right track. American Journal of Transplantation, 9(4), 655–656. https://doi.org/10.1111/j.1600-6143.2009.02572.x
8. Bohrium. (n.d.). Allorecognition direct and indirect pathways. SciencePedia.
9. Canadian Thoracic Society. (2026). 3.2. Interferon-gamma release assays. In Canadian tuberculosis standards.
10. Cavanagh, M., & Gwyer Findlay, E. (2022). T-cell activation. British Society for Immunology.
11. Cellular mechanisms, regulatory networks, and clinical diagnostics of cell-mediated immunity. (n.d.).
12. Centers for Disease Control and Prevention. (2024, May 9). Clinical testing guidance for tuberculosis: Interferon gamma release assay.
13. Cross-presentation of antigens by dendritic cells. (n.d.). PubMed.
14. Cross-presentation of cell-associated antigens by MHC class I in dendritic cell subsets. (n.d.). PubMed Central (PMC).
15. Divergence of tissue-memory T cells: Distribution and function-based classification. (n.d.). PubMed Central (PMC).
16. Elgueta, R., Benson, M. J., de Vries, V. C., Wasiuk, A., Guo, Y., & Noelle, R. J. (2009). Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunological Reviews, 229(1), 152–172. https://doi.org/10.1111/j.1600-065X.2009.00782.x
17. Embgenbroich, M., & Burgdorf, S. (2018). Current concepts of antigen cross-presentation. Frontiers in Immunology, 9, 1643. https://doi.org/10.3389/fimmu.2018.01643
18. Golden, D. (2022, June 21). Comparing immune checkpoint inhibitors and CAR T-cell therapies. Alliance for Cancer Gene Therapy.
19. Goldman, A. S., & Prabhakar, B. S. (1996). Immunology overview. In S. Baron (Ed.), Medical microbiology (4th ed.). University of Texas Medical Branch at Galveston.
20. IFN-γ induced the formation of foamy macrophages via CD40 signal to control Mycobacterium abscessus pulmonary infection. (n.d.). PubMed Central (PMC).
21. Imran, M., Alshrari, A. S., Khan, A., & Alzahrani, A. R. (2025). IFN-γ-driven macrophage responses in the immunity to Mycobacterium tuberculosis and Mycobacterium leprae. Frontiers in Cellular and Infection Microbiology, 15, 1679691. https://doi.org/10.3389/fcimb.2025.1679691
22. Influence of direct and indirect allorecognition pathways on CD4+CD25+ regulatory T-cell function in transplantation. (n.d.). PubMed Central (PMC).
23. Influence of environmental exposures on T follicular helper cell function and implications on immunity: A comparison of Bangladeshi and American children. (n.d.). mBio.
24. Interferon-gamma release assays (IGRAs) for testing for TB infection. (n.d.). Stop TB Partnership.
25. Janeway, C. A., Jr., Travers, P., Walport, M., & Shlomchik, M. J. (2001). Macrophage activation by armed CD4 TH1 cells. In Immunobiology: The immune system in health and disease (5th ed.). Garland Science.
26. Janeway, C. A., Jr., Travers, P., Walport, M., & Shlomchik, M. J. (2001). T cell-mediated immunity. In Immunobiology: The immune system in health and disease (5th ed.). Garland Science.
27. Lv, Y., Luo, X., Xie, Z., Qiu, J., Yang, J., Deng, Y., Long, R., Tang, G., Zhang, C., & Zuo, J. (2024). Prospects and challenges of CAR-T cell therapy combined with ICIs. Frontiers in Oncology, 14, 1368732. https://doi.org/10.3389/fonc.2024.1368732
28. Molecular mechanisms of T cell co-stimulation and co-inhibition. (n.d.). PubMed Central (PMC).
29. Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J. (2018). T cell allorecognition pathways in solid organ transplantation. Frontiers in Immunology, 9, 2548. https://doi.org/10.3389/fimmu.2018.02548
30. Sokolov, D. (2024, February 21). CAR-T cells and checkpoint inhibitors: Ripping out the breaks, or hitting the turbo? Fred Hutch Cancer Center.
31. T cell activation. (2024). Adapted from BioRender.com.
32. Th1 and Th17 cells in tuberculosis: Protection, pathology, and biomarkers. (n.d.). PubMed Central (PMC).
33. The regulation and role of T follicular helper cells in immunity. (n.d.). PubMed Central (PMC).
34. Tissue-resident memory T cells. (n.d.). PubMed.
35. Tissue-resident memory T cells. (n.d.). PubMed Central (PMC).
36. Uwadiae, F. I. (2021). T follicular helper cells. British Society for Immunology.
37. Wikipedia contributors. (2025, September 29). Alloantigen recognition. In Wikipedia, The Free Encyclopedia.
38. Wikipedia contributors. (2026, January 20). Cross-presentation. In Wikipedia, The Free Encyclopedia.
39. Wikipedia contributors. (2026, March 13). Interferon gamma release assay. In Wikipedia, The Free Encyclopedia.
40. Wikipedia contributors. (2026, January 31). Tissue-resident memory T cell. In Wikipedia, The Free Encyclopedia.
41. Wu, X., Wu, P., Shen, Y., Jiang, X., & Xu, F. (2018). CD8+ resident memory T cells and viral infection. Frontiers in Immunology, 9, 2093. https://doi.org/10.3389/fimmu.2018.02093
42. Zhang, S., Feng, Y., Wu, X., Chen, J., Zhang, H., Tian, L., Lou, H., Wang, L., Su, B., Huang, X., Qiu, L., Wu, D., Sha, W., & Lu, Z. (2025). IFN-γ induced the formation of foamy macrophages via CD40 signal to control Mycobacterium abscessus pulmonary infection. Frontiers in Immunology, 16, 1697443. https://doi.org/10.3389/fimmu.2025.1697443