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The TNF receptor-ligands 4-1BB-4-1BBL and GITR-GITRL in NK cell responses.

Barao I - Front Immunol (2013)

Bottom Line: Interactions between several tumor necrosis factor (TNF)-TNF receptor (TNFR) superfamily members that are expressed by T cells and natural killer (NK) cells and various other cell types modulate immune responses.This review summarizes the current understanding of how the TNF ligand-TNFR interactions 4-1BBL with 4-1BB, and GITRL with glucocorticoid-induced TNFR-related (GITR) regulate NK cell mediated antitumor responses and discuss its therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Nevada, Reno Reno, NV, USA.

ABSTRACT
Interactions between several tumor necrosis factor (TNF)-TNF receptor (TNFR) superfamily members that are expressed by T cells and natural killer (NK) cells and various other cell types modulate immune responses. This review summarizes the current understanding of how the TNF ligand-TNFR interactions 4-1BBL with 4-1BB, and GITRL with glucocorticoid-induced TNFR-related (GITR) regulate NK cell mediated antitumor responses and discuss its therapeutic implications.

No MeSH data available.


Related in: MedlinePlus

(A) Interactions of inhibitory and activating NK cell receptors, including TNF family receptors 4-1BB and GITR, with ligands expressed on leukemia cells. Engagement of the inhibitory receptors KIR and NKG2A with MHC class I molecules directly transmits inhibitory signals to the NK cells to reduce killing of tumors and IFN-γ production, whereas interactions of 4-1BB with 4-1BBL and GITR with GITRL can produce activating or inhibitory effects depending on conditions. Here their exclusively inhibitory effects upon interaction with leukemia cells are illustrated. Reverse signaling (by the bound ligands 4-1BBL and GITRL) to signal the leukemia cells induces the leukemic production of immunosuppressive cytokines such as TGF-β, TNF-α, and IL-10, which also suppress NK cell functions. Engagement of the activating NK cell receptors (NCRs) to their respective ligands and NKG2D to MICA/B or ULBPs on tumors transmits activating signals to NK cells and triggers their functions. Interactions between LFA-1 and ICAM-1 on the tumors promote cell-cell adhesion and activate NK cells. NK cell recognition of antibody-coated tumor cells by CD16 results in NK cell activation and tumor killing (ADCC). NK cells respond to cytokines such as IL-2, -15, or -21 by proliferating and increasing their functions. Activated NK cells can release lytic molecules such as perforin and granzymes upon engagement of target cells leading to necrosis and/or apoptosis of tumors. NK cells can also express TNF family proteins TRAIL and FasL, which binds death domain-containing TRAILR and Fas on tumors cells to induce tumor-cell apoptosis. (B) Therapeutic approaches to increase NK cell anti-leukemia effects. NK cell-mediated anti-leukemia activity can be enhanced by several approaches, including: (1) inactivation of KIR- and NKG2A-derived inhibitory signals using blocking mAbs; (2) blocking 4-1BB and GITR inhibitory signals using specific mAbs; (3) neutralization of 4-1BBL and GITRL effects on leukemia by competition with 4-1BB-Ig and GITR-Ig fusion proteins; and (4) ADCC with mAbs specific for tumor-associated antigens; and (5) IL-15 or IL-21 stimulation of cytotoxic activity. It should be noted that with approach 3, the R-Ig reagents may be able to stimulate the tumor productive of TGF-β and other immunosuppressive cytokines.
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Figure 1: (A) Interactions of inhibitory and activating NK cell receptors, including TNF family receptors 4-1BB and GITR, with ligands expressed on leukemia cells. Engagement of the inhibitory receptors KIR and NKG2A with MHC class I molecules directly transmits inhibitory signals to the NK cells to reduce killing of tumors and IFN-γ production, whereas interactions of 4-1BB with 4-1BBL and GITR with GITRL can produce activating or inhibitory effects depending on conditions. Here their exclusively inhibitory effects upon interaction with leukemia cells are illustrated. Reverse signaling (by the bound ligands 4-1BBL and GITRL) to signal the leukemia cells induces the leukemic production of immunosuppressive cytokines such as TGF-β, TNF-α, and IL-10, which also suppress NK cell functions. Engagement of the activating NK cell receptors (NCRs) to their respective ligands and NKG2D to MICA/B or ULBPs on tumors transmits activating signals to NK cells and triggers their functions. Interactions between LFA-1 and ICAM-1 on the tumors promote cell-cell adhesion and activate NK cells. NK cell recognition of antibody-coated tumor cells by CD16 results in NK cell activation and tumor killing (ADCC). NK cells respond to cytokines such as IL-2, -15, or -21 by proliferating and increasing their functions. Activated NK cells can release lytic molecules such as perforin and granzymes upon engagement of target cells leading to necrosis and/or apoptosis of tumors. NK cells can also express TNF family proteins TRAIL and FasL, which binds death domain-containing TRAILR and Fas on tumors cells to induce tumor-cell apoptosis. (B) Therapeutic approaches to increase NK cell anti-leukemia effects. NK cell-mediated anti-leukemia activity can be enhanced by several approaches, including: (1) inactivation of KIR- and NKG2A-derived inhibitory signals using blocking mAbs; (2) blocking 4-1BB and GITR inhibitory signals using specific mAbs; (3) neutralization of 4-1BBL and GITRL effects on leukemia by competition with 4-1BB-Ig and GITR-Ig fusion proteins; and (4) ADCC with mAbs specific for tumor-associated antigens; and (5) IL-15 or IL-21 stimulation of cytotoxic activity. It should be noted that with approach 3, the R-Ig reagents may be able to stimulate the tumor productive of TGF-β and other immunosuppressive cytokines.

Mentions: Natural killer (NK) cells are lymphocytes of the innate immune system that kill a variety of tumors and infected cells (by bacteria, parasites, and viruses) without prior sensitization to antigen and secrete cytokines that shape adaptive immune responses (Herberman et al., 1975; Kiessling et al., 1975; Vivier et al., 2008). Differing from T cells, NK cells lack antigen-specific receptors and bear a variety of cell surface activating and inhibitory receptors to recognize the cells that they kill and to regulate their functions (Figure 1A) (Lanier, 1998; Moretta et al., 2006; Baessler et al., 2010; Placke et al., 2010). In this review I will focus on how to exploit the inhibitory activity of tumor necrosis factor (TNF) receptors, 4-1BB and glucocorticoid-induced TNFR-related (GITR) in NK anti-leukemia activity to improve therapeutic NK cell intervention.


The TNF receptor-ligands 4-1BB-4-1BBL and GITR-GITRL in NK cell responses.

Barao I - Front Immunol (2013)

(A) Interactions of inhibitory and activating NK cell receptors, including TNF family receptors 4-1BB and GITR, with ligands expressed on leukemia cells. Engagement of the inhibitory receptors KIR and NKG2A with MHC class I molecules directly transmits inhibitory signals to the NK cells to reduce killing of tumors and IFN-γ production, whereas interactions of 4-1BB with 4-1BBL and GITR with GITRL can produce activating or inhibitory effects depending on conditions. Here their exclusively inhibitory effects upon interaction with leukemia cells are illustrated. Reverse signaling (by the bound ligands 4-1BBL and GITRL) to signal the leukemia cells induces the leukemic production of immunosuppressive cytokines such as TGF-β, TNF-α, and IL-10, which also suppress NK cell functions. Engagement of the activating NK cell receptors (NCRs) to their respective ligands and NKG2D to MICA/B or ULBPs on tumors transmits activating signals to NK cells and triggers their functions. Interactions between LFA-1 and ICAM-1 on the tumors promote cell-cell adhesion and activate NK cells. NK cell recognition of antibody-coated tumor cells by CD16 results in NK cell activation and tumor killing (ADCC). NK cells respond to cytokines such as IL-2, -15, or -21 by proliferating and increasing their functions. Activated NK cells can release lytic molecules such as perforin and granzymes upon engagement of target cells leading to necrosis and/or apoptosis of tumors. NK cells can also express TNF family proteins TRAIL and FasL, which binds death domain-containing TRAILR and Fas on tumors cells to induce tumor-cell apoptosis. (B) Therapeutic approaches to increase NK cell anti-leukemia effects. NK cell-mediated anti-leukemia activity can be enhanced by several approaches, including: (1) inactivation of KIR- and NKG2A-derived inhibitory signals using blocking mAbs; (2) blocking 4-1BB and GITR inhibitory signals using specific mAbs; (3) neutralization of 4-1BBL and GITRL effects on leukemia by competition with 4-1BB-Ig and GITR-Ig fusion proteins; and (4) ADCC with mAbs specific for tumor-associated antigens; and (5) IL-15 or IL-21 stimulation of cytotoxic activity. It should be noted that with approach 3, the R-Ig reagents may be able to stimulate the tumor productive of TGF-β and other immunosuppressive cytokines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539674&req=5

Figure 1: (A) Interactions of inhibitory and activating NK cell receptors, including TNF family receptors 4-1BB and GITR, with ligands expressed on leukemia cells. Engagement of the inhibitory receptors KIR and NKG2A with MHC class I molecules directly transmits inhibitory signals to the NK cells to reduce killing of tumors and IFN-γ production, whereas interactions of 4-1BB with 4-1BBL and GITR with GITRL can produce activating or inhibitory effects depending on conditions. Here their exclusively inhibitory effects upon interaction with leukemia cells are illustrated. Reverse signaling (by the bound ligands 4-1BBL and GITRL) to signal the leukemia cells induces the leukemic production of immunosuppressive cytokines such as TGF-β, TNF-α, and IL-10, which also suppress NK cell functions. Engagement of the activating NK cell receptors (NCRs) to their respective ligands and NKG2D to MICA/B or ULBPs on tumors transmits activating signals to NK cells and triggers their functions. Interactions between LFA-1 and ICAM-1 on the tumors promote cell-cell adhesion and activate NK cells. NK cell recognition of antibody-coated tumor cells by CD16 results in NK cell activation and tumor killing (ADCC). NK cells respond to cytokines such as IL-2, -15, or -21 by proliferating and increasing their functions. Activated NK cells can release lytic molecules such as perforin and granzymes upon engagement of target cells leading to necrosis and/or apoptosis of tumors. NK cells can also express TNF family proteins TRAIL and FasL, which binds death domain-containing TRAILR and Fas on tumors cells to induce tumor-cell apoptosis. (B) Therapeutic approaches to increase NK cell anti-leukemia effects. NK cell-mediated anti-leukemia activity can be enhanced by several approaches, including: (1) inactivation of KIR- and NKG2A-derived inhibitory signals using blocking mAbs; (2) blocking 4-1BB and GITR inhibitory signals using specific mAbs; (3) neutralization of 4-1BBL and GITRL effects on leukemia by competition with 4-1BB-Ig and GITR-Ig fusion proteins; and (4) ADCC with mAbs specific for tumor-associated antigens; and (5) IL-15 or IL-21 stimulation of cytotoxic activity. It should be noted that with approach 3, the R-Ig reagents may be able to stimulate the tumor productive of TGF-β and other immunosuppressive cytokines.
Mentions: Natural killer (NK) cells are lymphocytes of the innate immune system that kill a variety of tumors and infected cells (by bacteria, parasites, and viruses) without prior sensitization to antigen and secrete cytokines that shape adaptive immune responses (Herberman et al., 1975; Kiessling et al., 1975; Vivier et al., 2008). Differing from T cells, NK cells lack antigen-specific receptors and bear a variety of cell surface activating and inhibitory receptors to recognize the cells that they kill and to regulate their functions (Figure 1A) (Lanier, 1998; Moretta et al., 2006; Baessler et al., 2010; Placke et al., 2010). In this review I will focus on how to exploit the inhibitory activity of tumor necrosis factor (TNF) receptors, 4-1BB and glucocorticoid-induced TNFR-related (GITR) in NK anti-leukemia activity to improve therapeutic NK cell intervention.

Bottom Line: Interactions between several tumor necrosis factor (TNF)-TNF receptor (TNFR) superfamily members that are expressed by T cells and natural killer (NK) cells and various other cell types modulate immune responses.This review summarizes the current understanding of how the TNF ligand-TNFR interactions 4-1BBL with 4-1BB, and GITRL with glucocorticoid-induced TNFR-related (GITR) regulate NK cell mediated antitumor responses and discuss its therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Nevada, Reno Reno, NV, USA.

ABSTRACT
Interactions between several tumor necrosis factor (TNF)-TNF receptor (TNFR) superfamily members that are expressed by T cells and natural killer (NK) cells and various other cell types modulate immune responses. This review summarizes the current understanding of how the TNF ligand-TNFR interactions 4-1BBL with 4-1BB, and GITRL with glucocorticoid-induced TNFR-related (GITR) regulate NK cell mediated antitumor responses and discuss its therapeutic implications.

No MeSH data available.


Related in: MedlinePlus