Cytotoxic T cells in Apoptosis

Cytotoxic T cells: Defenders against infections and tumors

Cytotoxic T lymphocytes are powerful effectors of the adaptive immune system, acting as surveyors, detectors and destroyers of infected and abnormal, potentially cancerous cells. Their responses generate long-lived memory T cells, which remain poised for rapid reactivation upon antigen re-exposure, increasing the durability of immune defense.

How do cytotoxic T cells function?

Cells infected by a foreign agent such as a virus, or abnormal cells like tumor cells, display fragments of the agent on their cell surface as part of a complex with major histocompatibility complex class-1 (MHC-1). As circulating cytotoxic T cells scan the surface of antigen-presenting cells, they interact with MHC-1 via their CD8 receptor. Upon recognizing a foreign or abnormal peptide fragment, CTLs form a specialized immunological synapse with the target cell, polarizing their cytotoxic granules toward the target cell membrane.

At this immune synapse, CTLs release perforin, which oligomerizes to form transient pores in the target cell membrane. Through these pores, granzymes enter the target cell cytosol. Granzyme B directly activates caspase-3 and cleaves Bid into tBid, engaging the mitochondrial apoptosis pathway and amplifying cell death signals. Granzyme A, in contrast, induces a caspase-independent apoptosis pathway, causing single-stranded DNA damage and mitochondrial or ER stress.

CTLs additionally express Fas ligand (FasL), which clusters Fas death receptors at the immune synapse of the target cell, forming the DISC complex and activating caspase-8. This triggers the extrinsic apoptosis pathway, providing a second mechanism for inducing programmed cell death.

Once a target cell is eliminated, cytotoxic T lymphocytes are highly efficient “serial killers”: they detach, rapidly reload their cytotoxic granules through endocytosis and re-engage additional targets in succession.

How checkpoint inhibition of T cells work via CTLA-4 and PD-1/PD-L1

As powerful agents of the adaptive immune system, cytotoxic T cell activity must be carefully controlled to modulate the immune response and avoid damage to healthy cells and tissues. CTLA-4 is an immune checkpoint protein expressed on the surface of activated cytotoxic T lymphocytes that acts as a negative regulator of T-cell activation, inhibiting their proliferation. Cytotoxic T-lymphocyte protein 4 acts as a critical safeguard, preventing excessive immune responses that could lead to autoimmunity. In fact, CTLA-4 deficiency is a rare immune dysregulation syndrome that is characterized by immune system hyperactivity.

In addition to CTLA-4, CTLs are regulated by the PD-1/PD-L1 axis, another immune checkpoint that dampens CTL cytotoxicity. Tumor cells often exploit CTLA-4 and PD-1 signaling, using these checkpoints to evade detection by the immune system. Immune checkpoint inhibitor therapies have been developed to block CTLA-4 and PD-1/PD-L1, increasing overall CTL activity to boost immune responses against tumors (2).

Cytotoxic T cells vs natural killer cells

Both cytotoxic T lymphocytes and natural killer cells are involved in immune response aimed at destroying infected or abnormal cells, but they differ in their approach. T-killer cells are part of the adaptive immune system, which relies on antigen specificity and requires prior exposure to the pathogen to function effectively. In contrast, natural killer cells are part of the innate immune system that can recognize and kill abnormal, infected or stressed cells without the presence of a recognized antigen. Natural killer cells are critical for early defense, providing time for adaptive immunity to become fully activated (3).  

What is the difference between CD4+ T cells and CD8+ T cells (CD4+ vs CD8+)?

CD4+ and CD8+ T cells provide critical support to the adaptive immune system by coordinating effective immune responses. They also directly target infections and cancer cells, helping the body protect itself and maintain health.

T cells have traditionally been divided into two groups: cytotoxic T cells and helper T cells. Cytotoxic T cells express the CD8 receptor and are therefore sometimes referred to as CD8 cytotoxic T cells, CD8+ cytotoxic T cells or CD8+ T cells. As described in detail above, these cells directly attack pathogens.

In contrast, T helper cells express the CD4 receptor. Sometimes referred to as CD4+ T cells, this subset of T cells are best known for helping to coordinate the immune response by other cells without attacking pathogens directly. However, recent research has found that a small subset of CD4+ T cells also exhibits cytotoxic capabilities. Known as CD4 cytotoxic T cells, or CD4+ cytotoxic T cells, this subset of T cells has characteristics of both helper and cytotoxic T cells (4).

References

1. Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359–367.
2. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;59(6382):1350–1355.
3. Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer immunotherapy based on natural killer cells: Current progress and new opportunities. Front Immunol. 2019;10:1205.
4. Hoeks C, Duran G, Hellings N, Broux B. When helpers go above and beyond: Development and characterization of cytotoxic CD4+ T cells. Front Immunol. 2022;13:951900.