CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction

Trzonkowski, Piotr; Szmit, Ewa; Myśliwska, Jolanta; Dobyszuk, Anita; Myśliwski, Andrzej

doi:10.1016/j.clim.2004.04.003

Cited by 186 publications

(103 citation statements)

References 23 publications

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“…Although earlier studies have suggested a role for Treg in suppressing NK cell effector functions in vitro (6,32,33), we have defined at least one mechanism by which activated Treg can directly suppress NK cell function via the NKG2D pathways in vivo. We have extended the implications further by illustrating that relief of that Treg suppression can greatly enhance the functional activity of NK cells responding to the activating IL-12 cytokine, which is known to enhance the NKG2D pathway of NK cell activation (31).…”

Section: Discussionmentioning

confidence: 99%

CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer

Smyth

Teng

Swann

et al. 2006

The Journal of Immunology

376

288

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CD4+CD25+ regulatory T cells (Treg) that suppress T cell-mediated immune responses may also regulate other arms of an effective immune response. In particular, in this study we show that Treg directly inhibit NKG2D-mediated NK cell cytotoxicity in vitro and in vivo, effectively suppressing NK cell-mediated tumor rejection. In vitro, Treg were shown to inhibit NKG2D-mediated cytolysis largely by a TGF-β-dependent mechanism and independently of IL-10. Adoptively transferred Treg suppressed NK cell antimetastatic function in RAG-1-deficient mice. Depletion of Treg before NK cell activation via NKG2D and the activating IL-12 cytokine, dramatically enhanced NK cell-mediated suppression of tumor growth and metastases. Our data illustrate at least one mechanism by which Treg can suppress NK cell antitumor activity and highlight the effectiveness of combining Treg inhibition with subsequent NK cell activation to promote strong innate antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer

Smyth

Teng

Swann

et al. 2006

The Journal of Immunology

376

288

View full text Add to dashboard Cite

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“…At the cellular level, Tregs suppress the activation and proliferation of CD4 þ and CD8 þ T cells, [30][31][32] by inhibition of interleukin (IL)-2 production and induction of cell cycle arrest in these cells, which requires cell-cell contact. 32 In contrast, in vivo studies report that the presence of cytokines, such as IL-10 and TGF-b, might also be necessary for a suppressive milieu.…”

Section: Discussionmentioning

confidence: 99%

FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival

et al. 2007

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FOXP3 is a unique marker for CD4 þ CD25 þ regulatory T cells (Tregs). In solid tumours, high numbers of Tregs are associated with a poor prognosis. Knowledge about the implications of Tregs for the behaviour of haematological malignancies is limited. In this study, skin biopsies from 86 patients with mycosis fungoides (MF) and cutaneous T-cell lymphoma (CTCL) unspecified were analysed for the expression of FOXP3 on tumour cells and tumour-infiltrating Tregs. Labelling of above 10% of the neoplastic cells was seen in one case classified as an aggressive epidermotropic CD8 þ cytotoxic CTCL. In the remaining 85 cases, the atypical neoplastic infiltrate was either FOXP3 negative (n ¼ 80) or contained only very occasional weakly positive cells (n ¼ 5). By contrast, all biopsies showed varying numbers of strongly FOXP3 þ tumour-infiltrating Tregs. MF with early or infiltrated plaques had significantly higher numbers of FOXP3 þ Tregs than CTCL unspecified or advanced MF with tumours or transformation to large cell lymphoma. An analysis of all patients demonstrated that increasing numbers of FOXP3 þ Tregs were associated with improved survival in both MF and CTCL unspecified. In conclusion, our data indicate that the presence of FOXP3 þ Tregs in CTCL is associated with disease stage and patient survival.

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“…[10][11][12] In contrast to these suppressive cytokines, several cytokines such as IL-2, IL-12, IL-15, IL-18, and IL-21 are known to activate NK cells both in vitro and in vivo, and are proposed to increase the therapeutic potential of these cells for adoptive therapy. 13 Due to their natural cytotoxic property in the peripheral blood, 14 the use of NK cells has been identified as one of the promising adoptive cellular immunotherapies to control cancer.…”

Section: Cd11bmentioning

confidence: 99%

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

et al. 2016

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Natural killer (NK) cells are known to have effector and cytolytic properties to kill virus infected or tumor cells spontaneously. Due to these properties, NK cells have been used as an adoptive cellular therapy to control tumor growth in various clinical trials but have shown limited clinical benefits. This indicates that our knowledge about phenotypic and functional differences in NK cells within the tumor microenvironment and secondary lymphoid tissues is incomplete. In this work, we report that B16F10 cellinduced melanoma recruits the CD11b C CD27C subset of NK cells at a very early stage during tumor progression. These intratumoral NK cells showed increased expression of CD69, reduced inhibitory receptor KLRG1, and decreased proliferative ability. As compared to splenic NK cells, intratumoral NK cells showed decreased expression of activating receptors NKG2D, Ly49D and Ly49H; increased inhibitory receptors, NKG2A and Ly49A; decreased cytokines IFNg and GM-CSF; decreased cytokine receptors IL-21R, IL-6Ra, and CD122 expression. Depletion of NK cells led to decrease peripheral as well as intratumoral effector CD4 C T-bet C cells (Th1), and increased tumor growth. Furthermore, purified NK cells showed increased differentiation of Th1 cells in an IFNg-dependent manner. Anti-NKG2D in the culture promoted differentiation of effector Th1 cells. Collectively, these observations suggest that intratumoral NK cells possess several inhibitory functions that can be partly reversed by signaling through the NKG2D receptor or by cytokine stimulation, which then leads to increased differentiation of effector Th1 cells.

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CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction

Cited by 186 publications

References 23 publications

CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer

CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer

FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

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