Cell mediated immune response- self MHC restriction, T cell activation, co-stimulatory signals, killing mechanism by CTL and NK cells

Cell mediated immune response- self MHC restriction, T cell activation, co-stimulatory signals, killing mechanism by CTL and NK cells

Cell-Mediated Immunity  

Cell-mediated immunity (CMI) is the branch of the adaptive immune system directed against intracellular pathogens (viruses, intracellular bacteria, parasites), altered-self cells (tumour cells), and graft tissue.

Cell-mediated immunity relies on both antigen-specific lymphocytes (CD4 TH cells and CD8 Cytotoxic T Lymphocytes) and non-specific effector cells (NK cells, macrophages, neutrophils, and eosinophils).  Local cytokines secreted primarily by T cells, NK cells, and macrophages coordinate and sustain the activity of all these cells.  Cell-mediated and humoral immunity actively cooperate: non-specific immune cells use antibodies to target cells for killing (ADCC), and complement activation (in response to antigen-antibody complexes) recruits leukocytes to the site of infection.

Cell-mediated immune responses fall into two broad functional categories based on their effector cells:

• Direct Cytotoxic Effectors (Target Lysis): Cells that directly eliminate foreign, malignant, virus-infected, or chemically modified cells through cytolytic reactions.  These cells directly destroy virally infected cells, tumor cells, and foreign tissue grafts by triggering targeted apoptosis via the perforin/granzyme or Fas/FasL pathways.
• Antigen-Specific:  CD8+ Cytotoxic T Lymphocytes (CTLs).
• Antigen-Nonspecific: Natural Killer (NK) cells and activated macrophages.
• Delayed-Type Hypersensitivity (TH Effectors): A specialized subpopulation of effector CD4+ T cells that mediate inflammatory responses and macrophage activation rather than direct cell lysis.  They release potent inflammatory cytokines (IFN-γ and TNF-α) to activate tissue macrophages, recruit granulocytes, and wall off persistent intracellular microbes.

Self-MHC Restriction of T Cells

T lymphocytes do not recognize free, soluble antigen. Their αβ TCRs recognise antigen only as degraded peptide fragments presented by self-MHC molecules.  This is termed self-MHC restriction.

Feature	CD4+ Helper T Cell (TH​)	CD8+ Cytotoxic T Cell (TC​ / CTL)
Co-receptor	CD4	CD8
MHC Restriction	MHC Class II	MHC Class I
Antigen Source	Exogenous (extracellular pathogens)	Endogenous (intracellular/viral / tumour)
Presented by	Professional APCs only (Dendritic cells, Macrophages, B cells)	All nucleated cells (any infected target cell)
Primary Function	Secretes cytokines to help B cells and activate macrophages	Directly kills infected or abnormal target cells via apoptosis

 

 Generation of the MHC-Restricted Repertoire in Thymus

Self-MHC restriction is acquired during T-cell maturation in the thymus through a two-step selection process to produce functional, non-autoreactive T cells:

• Positive Selection (Cortex): Immature double-positive (CD4+ CD8+) thymocytes interact with cortical epithelial cells displaying self-MHC Class I and II molecules. Cells with T-cell receptors (TCRs) that recognise self-MHC with low-to-moderate affinity receive essential survival signals, while non-binding cells die by neglect; this step establishes self-MHC restriction.  Thymocytes lose their double-positive (CD4+ CD8+) nature during and following positive selection in the thymic cortex, as they transition into single-positive (CD4+ or CD8+) cells.
• Negative Selection (Cortex and Medulla): Surviving thymocytes are screened by dendritic cells and macrophages presenting self-peptides on self-MHC. Thymocytes whose TCRs bind self-antigens with high affinity are eliminated via apoptosis (clonal deletion); this step establishes central self-tolerance.

After completing positive and negative selection in the thymus, surviving single-positive (CD4+ or CD8+) T cells exit into the peripheral circulation as naive T cells. Upon encountering their specific antigen, they proliferate and differentiate into effector T cells.

How a Naive T Cell Becomes Effector and Memory Cells

1.    Activation - A naive T cell in a lymph node encounters a dendritic cell displaying specific antigen alongside co-stimulatory signals. This triggers rapid cell division (clonal expansion).

2.    Effector Differentiation - Most of the dividing cells become effector T cells (TC or CTLs). They leave the lymph nodes, travel to the infected tissue, and actively clear the pathogen by secreting cytokines or killing infected cells. Once the infection is eliminated, over 90% of these effector cells die off by apoptosis.

3.   Memory Cell Formation - A small subset (5-10%) of the cells survives and differentiates into memory T cells. Supported by survival cytokines (IL-7 and IL-15), they live for years or decades to provide immediate, highly potent protection upon reexposure.

Cytotoxic T Cells

Cytotoxic T lymphocytes, or CTLs, are generated by immune activation of T cytotoxic (TC) cells. These effector cells have lytic capability and are critical in the recognition and elimination of altered self-cells.  Since all nucleated cells in the body express class I MHC molecules, CTLs can recognize and eliminate almost any altered body cell.

The CTL-mediated immune response can be divided into two phases, reflecting different aspects of the response. The first phase activates and differentiates naive TC cells into functional effector CTLs. In the second phase, effector CTLs recognise antigen–class I MHC complexes on specific target cells, which leads them to destroy the target cells.

Naive TC cells are incapable of killing target cells and are therefore referred to as CTL precursors (CTL-Ps).

Naive T-cell activation occurs through an immunological synapse formed with an antigen-presenting cell (APC), where multiple receptor–ligand pairs cluster together.  Generation of CTLs from CTL-Ps requires at least three sequential signals  

1. An antigen-specific signal 1 transmitted by the TCR complex upon recognition of a peptide–class I MHC molecule complex

2. A co-stimulatory signal transmitted by the CD28-B7 interaction of the CTL-P and the antigen-presenting cell

3. A signal induced by the interaction of IL-2 with the high-affinity IL-2 receptor, resulting in proliferation and differentiation of the antigen-activated CTL-P into effector CTLs

Generation of effector CTLs (Kuby Immunology) 

While naive cytotoxic T-lymphocyte precursors (CTL-Ps) rely on TH cells for IL-2 and enhanced CD28–B7 co-stimulation to proliferate, memory CTL-Ps can auto secrete sufficient IL-2 and differentiate into effector CTLs without needing TH help or CD28–B7 co-stimulation.

Cytotoxic T Lymphocytes (CD8+ CTLs) eliminate virus-infected, tumor, and foreign cells by inducing programmed cell death (apoptosis) via two primary pathways

(a)  The Fas pathway. Interaction of the membrane-bound Fas ligand on CTLs with the Fas receptor on the surface of target cells.  Ligation of trimeric Fas units by CTL-borne Fas ligand leads to the association of the death domains of Fas with FADD, which in turn results in a series of reactions leading to apoptosis of the target cell.

(b)  The perforin/granzyme pathway. Directional delivery of cytotoxic proteins (perforin and granzymes) that are released from CTLs and enter target cells.  Granule exocytosis releases granzymes and perforin from the CTL into the space between the CTL and the target cell. Granzyme B enters the target cell in two ways: via perforin-generated pores, or by binding to mannose 6-phosphate receptors that are subsequently endocytosed. Granzyme B is then released into the cytoplasm in a perforin-dependent process. Cleavage of procaspase 8 by granzyme B activates a caspase cascade that results in the apoptotic death of the cell, and interaction of granzyme B with other targets can invoke mitochondrially mediated death pathways. While Granzyme B rapidly kills targets by activating the caspase cascade, many viruses and tumors have evolved caspase inhibitors to block this process. To counteract this, CTLs also load their granules with Granzyme A, providing a guaranteed, caspase-independent pathway that destroys the target cell's mitochondria and DNA if the primary pathway is blocked.

Either of these events results in the activation of a signalling pathway that culminates in the death of the target cell by apoptosis

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