IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo

Hara, Masaki; Kingsley, Cherry I.; Niimi, Masanori; Read, Simon; Turvey, Stuart E.; Bushell, Andrew; Morris, Peter J.; Powrie, Fiona; Wood, Kathryn J.

doi:10.4049/jimmunol.166.6.3789

Cited by 720 publications

(570 citation statements)

References 67 publications

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“…Treg can interact with other immune populations via soluble factors and/or via cell-contactdependent mechanisms. Whereas in vivo studies have suggested a major role for soluble factors, such as IL-10 [41], TGF-b [42], or IL-35 [43], most in vitro experiments described a cell-contactdependent mechanism, involving CTLA-4 [44,45], GITR [46], Perforin [33], or Granzyme B [34]. Our data suggest that Perforin/ Granzyme-induced apoptosis does not play a major role in Tregmediated suppression of mouse gd-T-cell activity.…”

Section: Discussionmentioning

confidence: 51%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

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Section: Discussionmentioning

confidence: 51%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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“…It inhibits cytokine production and proliferation of CD4 þ T cells 7 and reduces expression of major histocompetibility complex (MHC) class II, intracellular adhesion molecule (ICAM)-1 and CD80 on dendritic cells (DCs), resulting in induction of T-cell anergy 8,9 or regulatory T (Tr) cells that suppress antigen-specific T-cell responses 10,11 IL-10 was found in many human tumors 12,13 It has been demonstrated that tumor-induced IL-10 (i) blocks tumor-specific helper T type 1 (Th1) responses, 14 (ii) inhibits tumor-specific CD8 þ CTL cytotoxicity 15 and (iii) supports the tumor growth. 16 in animal tumor models.…”

Section: Introductionmentioning

confidence: 99%

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

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T-cell suppression derived from tumor-secreted immunosuppressive interleukin (IL)-10 becomes a major barrier to CD8 þ T-cell immunotherapy of tumors. Tumor necrosis factor-alpha (TNF-a) is a multifunctional cytokine capable of activating T and dendritic cells (DCs) and counteracting IL-10-mediated DC inhibition and regulatory T-cell-mediated immune suppression. In this study, we constructed a recombinant adenovirus MF AdVTNF with fiber-gene modified by RGD insertion into the viral knob's H1 loop and a melanoma cell line B16 OVA/ILÀ10 engineered to express ovalbumin (OVA) and to secrete IL-10 (2.2 ng/ml/10 6 cells/24 h). We transfected OVA-specific CD8 þ T cells with MF AdVTNF, and found a fivefold increase in transgene human TNF-a secretion (4.3 ng/ ml/10 6 cells/24 h) by the engineered CD8 þ T TNF cells transfected with MF AdVTNF, compared to that (0.8 ng/ml/10 6 cells/24 h) by CD8 þ T cells transfected with the original AdVTNF without viral fiber modification. The engineered CD8 þ T TNF cells exhibited enhanced cytotoxicity and elongated survival in vivo after adoptive transfer. TNF-a derived from both the donor CD8 þ T cells and the host cells plays an important role in donor CD8 þ T-cell survival in vivo after adoptive transfer. We also demonstrated that the transfected B16 OVA/ILÀ10 tumor cells secreting IL-10 are more resistant to in vivo CD8 þ T-cell therapy than the original B16 OVA tumor cells without IL-10 expression. Interestingly, the engineered CD8 þ T TNF cells secreting transgene-coded TNF-a, but not the control CD8 þ T control cells without any transgene expression eradicated IL-10-secreting 12-day lung micrometastasis in all 10/10 mice and IL-10-secreting solid tumors (B5 mm in diameter) in 6/10 mice. Transfer of the engineered CD8 þ T TNF cells further induced both donor-and host-derived memory CD8 þ T cells, leading to a stronger long-term antitumor immunity against the IL-10-secreting B16 OVA/ILÀ10 tumor cell challenges. Therefore, CD8 þ T cells engineered to secrete TNF-a may be useful when designing strategies for adoptive T-cell therapy of solid tumors.

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“…To address this question, further studies are needed to include either preincubating APC with vIL-10 or preincubating T cells with vIL-10, before MLR challenge. vIL-10 may induce regulatory T cells to mediate tolerance 31 but, in this study and using flow cytometry, we were unable to detect CD4+CD25+ regulatory T cells in the in vitro coculture system (data not shown). What is clear from our data is that it is the timing of the vIL-10 intervention that is much more important than the dose.…”

Section: Discussionmentioning

confidence: 58%

Lentivirus-mediated gene transfer of viral interleukin-10 delays but does not prevent cardiac allograft rejection

et al. 2005

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IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo

Cited by 720 publications

References 67 publications

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Lentivirus-mediated gene transfer of viral interleukin-10 delays but does not prevent cardiac allograft rejection

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