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†Present address: Michele Ardolino, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3200, USA.
This article was submitted to Frontiers in NK Cell Biology, a specialty of Frontiers in Immunology.
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The negative regulation of adaptive immunity is relevant to maintain lymphocyte homeostasis. Several studies on natural killer (NK) cells have shown a previously unappreciated immunomodulatory role, as they can negatively regulate T cell-mediated immune responses by direct killing and by secretion of inhibitory cytokines. The molecular mechanisms of T cell suppression by NK cells, however, remained elusive. Only in the last few years has it become evident that, upon activation, human T cells express MICA–B, ULBP1–3, and PVR, ligands of the activating receptors NKG2D and DNAM-1, respectively. Their expression renders T cells targets of NK cell lysis, representing a new mechanism taking part to the negative regulation of T cell responses. Studies on the expression of NKG2D and DNAM-1 ligands on T cells have also contributed in understanding that the activation of ATM (ataxia-telangiectasia, mutated)/ATR (ATM/Rad3-related) kinases and the DNA damage response is a common pathway regulating the expression of activating ligands in different types of cells and under different conditions. The functional consequences of NKG2D and DNAM-1 ligand expression on activated T cells are discussed in the context of physiologic and pathologic processes such as infections, autoimmunity, and graft versus host disease.
Natural killer (NK) cells contribute to the suppression of T cell responses and to the maintenance of T lymphocyte homeostasis through the release of inhibitory cytokines, such as TGF-β and IL-10, which can inhibit dendritic cell (DC) maturation or T cell activation and functions, and/or through the direct elimination of antigen-presenting cells and activated T cells (
NKG2D is an activating receptor expressed on NK cells, CD8+ T cells and γ/δ T cells that binds to several inducible self-proteins belonging to the MIC (MICA, MICB) and ULBP (ULBP1 to ULBP6) families in humans, and H60 (a–c), Rae (α-ε) and MULT1 in mice (
Different stimuli implicated in the induction or up-regulation of NKG2D and DNAM-1 ligands on activated T cells.
Human | anti-CD3 plus anti-CD28 | MICA/B, |
PVR | T cells | |
Superantigen, alloantigen, |
MICA/B, |
CD4+ and |
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Anti-CD3 plus IL-2 | MICA | CD8+ T cells | |||
Superantigen | PVR, Nectin-2 | T cells | |||
PHA | PVR | CD4+ T cells | |||
Histone deacetylase inhibitors | MICA/B | Jurkat and activated |
|||
Propionic acid | MICA/B | Jurkat and activated |
|||
ULBP-1 | Treg | ||||
HIV | MICA, |
Jurkat and activated |
|||
HIV | PVR | Activated CD4+ T cells | |||
Mouse | mHA antigen | H60, MULT1 | CD4+ T cells | ||
ConA, PMA/ionomycine, ovalbumin | H60 | T cells |
DNAM-1/CD226 is an activating receptor belonging to the Ig superfamily and is constitutively expressed by most NK cells, T cells, macrophages, and DCs. DNAM-1 interacts with LFA-1, required for its functional activity on both NK and cytotoxic T cells (
NKG2DL expression is tightly regulated at various levels. During malignant transformation, cells undergo genotoxic or other forms of cellular stress with
Increasing evidences show the involvement of DDR in many physiological processes, such as mitosis (
A plethora of studies analyzed the role of NKG2D/NKG2DL axis by looking at infected cells, which very often express one or more ligands. These studies have demonstrated that NKG2D plays an important role in anti-viral immunity, via a direct NK cell-mediated lysis of infected cells. This evidence is also underscored by the countermeasures taken by viruses to avoid NKG2D-mediated triggering (
Considering HIV-1, a virus replicating (among other cell types) in CD4+ T lymphocytes, we face a situation where NK cell targeting of activated T cells via NKG2D means, at the same time, eliminating the infected cell. In fact, expression of several NKG2DLs was observed on HIV-1 infected CD4+ T cells, with increased susceptibility to NK lysis (
The role of DNAM-1 and its ligands in the context of NK–T cell interactions during viral infections has been less investigated. Recently, PVR was detected on HIV-1 infected CD4+ T cells, and when the NKG2D pathway was inhibited, additional blocking of DNAM-1 strongly impaired the capacity of NK cells to kill HIV-1-infected cells, indicating the involvement of both receptors (
The mechanisms by which NK cells modulate adaptive immune responses in the course of autoimmune diseases have been addressed by a large number of
Thinking in terms of negative regulation of (autoreactive) T cell responses, NK cells might exert a direct effect on activated, autoantigen-specific T cells. In experimental autoimmune encephalomyelitis (EAE),
A number of studies have identified the cytolytic mechanism underlying NK cell-mediated killing of autoreactive T cells, and the NK cell-mediated immunoregulatory activity was shown to be perforin-dependent in animal models of colitis, EAE, and CIA (
The role of NKG2D/NKG2DLs in autoimmunity has been addressed also from another point of view. In fact, endogenous cells and/or tissues can aberrantly express NKG2DLs (as shown in particular for MICA and MICB in humans and Rae-1 in mice), promoting activation of autoreactive infiltrating NKG2D+ T cells, leading to tissue destruction. Examples of this condition can be found in human type I diabetes and in NOD mice, in patients with rheumatoid arthritis, Crohn’s disease, celiac disease, and in a mouse model of autoimmune vitiligo. These aspects are however reviewed elsewhere (
Regarding DNAM-1, despite the expression of PVR on activated T cells (
Allogeneic bone marrow transplantation (BMT) was estimated to be an effective treatment for hematologic malignancies and some solid tumors. However, the high incidence of graft versus host disease (GVHD) mediated by the activation and proliferation of alloreactive T cells leads to severe host tissue damage. Previous studies demonstrated that donor NK cells are able to suppress the development of GVHD through the killing of host antigen-presenting cells which are essential for donor T cell activation (
In summary, a central role for NK cell killing in mediating immunoregulatory effects is emerging. Studies of different conditions (infections, autoimmunity, transplants) indicate that NK cytotoxicity of activated T cells, as well as of other cells of the immune system, is important in immune regulation. The involvement of NKG2D and DNAM-1 receptors may represent the “tip of the iceberg,” with significant effects on the negative regulation of adaptive T cell responses, resulting in increased viral burdens, viral persistence, and/or inflammation. The locations where these events take place, and which are the NK cell subsets involved are still rather obscure parts of the picture.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors are supported by grants of the Italian Ministry of Health (Giovani Ricercatori n. 000307 to Alessandra Zingoni), the Italian Association for Cancer Research (AIRC), AIRC 5x1000, and the “Sapienza” University of Rome. Michele Ardolino is a recipient of a fellowship from Istituto Pasteur-Fondazione Cenci-Bolognetti.