Natural Killer T Cell

• NKT cells are specialized lymphocytes sharing features of both T cells and natural killer (NK) cells.
• They uniquely recognize lipid antigens presented by CD1d molecules, distinguishing them from conventional T cells.
• These cells are crucial for rapid immune responses, producing a broad spectrum of cytokines upon activation.
• Their functions encompass anti-tumor immunity, defense against infections, and regulation of autoimmune conditions.
• NKT cells are primarily categorized into Type I (invariant) and Type II (variant) based on their T cell receptor diversity and functional roles.

What is a Natural Killer T Cell?

A Natural Killer T Cell (NKT cell) refers to a distinct lineage of T lymphocytes that possess characteristics of both conventional T cells and natural killer (NK) cells. Unlike conventional T cells, which recognize peptide antigens presented by Major Histocompatibility Complex (MHC) molecules, NKT cells recognize lipid antigens presented by the non-polymorphic CD1d molecule. This unique antigen recognition pathway allows NKT cells to respond rapidly to a wide range of threats. They express a T cell receptor (TCR) but also carry markers typically found on NK cells, such as NK1.1 in mice, making them a bridge between the innate and adaptive immune systems.

These cells are relatively rare, typically constituting less than 1% of peripheral blood T cells in humans, yet their potent and rapid effector functions make them disproportionately important in immune responses. Their ability to quickly produce large amounts of cytokines upon activation allows them to modulate the activity of many other immune cells, including NK cells, B cells, and dendritic cells.

Function and Role of Natural Killer T Cells

The primary function of natural killer T cells is to act as rapid responders in the immune system, initiating and modulating immune responses against various challenges. Their activation leads to the swift production of a diverse array of cytokines, such as interferon-gamma (IFN-γ) and interleukin-4 (IL-4), which can either promote pro-inflammatory or anti-inflammatory responses, depending on the context.

The multifaceted role of natural killer T cells includes:

• Anti-tumor Immunity: NKT cells can directly kill tumor cells and also release cytokines that enhance the anti-tumor activity of other immune cells, such as NK cells and cytotoxic T lymphocytes.
• Anti-pathogen Defense: They play a crucial role in defending against a variety of pathogens, including bacteria (e.g., Mycobacterium tuberculosis), viruses (e.g., herpes simplex virus), and parasites. Their rapid response helps control initial infection and shapes subsequent adaptive immunity.
• Immunoregulation: NKT cells are involved in regulating autoimmune diseases, allergic reactions, and transplant rejection. Depending on their activation state and cytokine profile, they can either suppress or exacerbate immune pathology. For instance, in some autoimmune conditions, NKT cells can help suppress disease progression, while in others, their dysregulation might contribute to pathogenesis.

This dual capacity to both promote and suppress immune responses highlights their critical regulatory role in maintaining immune homeostasis.

Types of Natural Killer T Cells

Natural killer T cell types are primarily categorized into two major groups based on the diversity of their T cell receptors (TCRs) and their antigen specificity: Type I NKT cells and Type II NKT cells.

Type I NKT cells, also known as invariant NKT (iNKT) cells, are characterized by a highly conserved TCR alpha chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a limited repertoire of beta chains. These cells are activated by a specific lipid antigen, alpha-galactosylceramide (αGalCer), presented by CD1d. Upon activation, iNKT cells rapidly produce large amounts of both Th1-type (e.g., IFN-γ) and Th2-type (e.g., IL-4) cytokines, making them potent modulators of immune responses. They are extensively studied for their roles in anti-tumor immunity and anti-microbial defense.

Type II NKT cells, also referred to as variant NKT cells, express a more diverse TCR repertoire compared to Type I NKT cells. Their antigen specificity is broader, recognizing a wider range of endogenous and exogenous lipid antigens presented by CD1d. Type II NKT cells generally produce a different cytokine profile, often associated with regulatory or suppressive functions, and are thought to play significant roles in modulating inflammation and autoimmunity. While less well-characterized than Type I NKT cells, ongoing research continues to uncover their distinct contributions to immune system regulation and disease pathogenesis.