Natural Killer T-like Cells: Immunobiology and Role in Disease

Abstract

CD56+ T cells are generally recognized as a distinct population of T cells and are categorized as NKT-like cells. Although our understanding of NKT-like cells is far from satisfactory, it has been shown that aging and a number of disease situations have impacted these cells. To construct an overview of what is currently known, we reviewed the literature on human NKT-like cells. NKT-like cells are highly differentiated T cells with "CD1d-independent" antigen recognition and MHC-unrestricted cell killing. The genesis of NKT-like cells is unclear; however, it is proposed that the acquisition of innate characteristics by T cells could represent a remodeling process leading to successful aging. Additionally, it has been shown that NKT-like cells may play a significant role in several pathological conditions, making it necessary to comprehend whether these cells might function as prognostic markers. The quantification and characterization of these cells might serve as a cutting-edge indicator of individual immune health. Additionally, exploring the mechanisms that can control their killing activity in different contexts may therefore result in innovative therapeutic alternatives in a wide range of disease settings.

Keywords: ageing; autoimmunity; cancer; infection; inflammation; innate-like cells; natural killer T-like cells; neurological disorders; pregnancy; transplantation.

Figure 1

Receptor repertoire of NKT-like cells. NKT-like cells are T cells that acquire the expression of the CD56 molecule, as a typical marker of NK cells. In the middle of the image, it the receptor repertoire of NKT-like cells is presented, to the left, the receptor repertoire of T cells that are common to NKT-like cells is shown, and to the right, the receptor repertoire of NK cells that are common to NKT-like cells can be seen. T and NK cells are categorized as having an adaptive and innate immunity, respectively, whereas NKT-like cells are categorized with innate-like immunity, since NKT-like cells share mechanisms from both T and NK cells. The mature phenotype of NKT-like cells (CD45RA and CD57) includes a number of activating and inhibitory receptors (NCR, KIR, NKG2A/C/D, αβ TCR and IL2Rβ). NKT-like cells also have a high capacity for cytokine production and cytotoxicity. Blue and green circles represent granules and cytokines, respectively. TCR—T cell receptor; NCR—natural cytotoxic receptor; KIR—killer-cell immunoglobulin-like receptor.

Figure 2

Illustration of the hypothesis that the age-related increase in NKT-like cells may result from long-term antigen exposure. In general, the TCR and CD28-dependent activity of classical T cells declines with age; conversely, NKT-like cells accumulate in the peripheral blood. Although the genesis of NKT-like cells is unknown, it has been hypothesized that the persistent antigen exposure of T cells may result in the acquisition of innate-like receptors, such as CD56. It is speculated that this mechanism, which is intimately tied to aging, occurs as an immunological remodeling process, and may assist or at the very least be associated with successful aging. Blue and green circles represent granules and cytokines, respectively.

Figure 3

Illustration of the properties of NKT-like cells. NKT-like cells become activated when exposed to IL-15 and IL-23, but less so when exposed to IL-2, IL-12, IL-18, anti-CD3, and anti-CD137. IFN-γ and TNF-α are strongly produced in response to the majority of these molecules, and NKT-like cells also secrete IL-2, IL-5, IL-6, and IL-13. Mast cells secrete cytokines (CCL3, CCL4, and CCL5) attract NKT-like cells to the injured site. On the other hand, the production of soluble FasL may trigger the recruitment of additional immune cells such as neutrophils and monocytes. The effector function of NKT-like cells is regulated by the recognition of target cells through the TCR, KIR, NKG2A/C, and NKG2D receptors. When activated, NKT-like cells also release granules, such as perforin-1 and granzyme B, which are the path of choice to kill target cells. TCR—T cell receptor; KIR—killer-cell immunoglobulin-like receptor; sFasL—soluble FasL.