The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells

Wüest, Thomas; Willette-Brown, Jami; Durum, Scott K.; Hurwitz, Arthur A.

doi:10.1189/jlb.1107778

Cited by 83 publications

(71 citation statements)

References 52 publications

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“…Besides acting directly on NKT cells and enhancing their activity against TAMs, locally produced IL-15 is expected to activate other antitumor immune effector cells, such as NK and tumor-specific CD8 + T cells (55). In contrast to IL-2, IL-15 does not fully activate Tregs (56), which are known to have an inhibitory effect on NKT cells (57) and could counteract their antitumor activity. To ensure the safety of the potential clinical use of NKT/IL-15 cells, we incorporated a suicide gene, iCasp-9, which allows the elimination of transgeneic cells upon its pharmacologic activation with a nontoxic small molecular drug, AP20187 (58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

et al. 2012

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Section: Discussionmentioning

confidence: 99%

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

et al. 2012

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“…23,24 Our finding that IL-21 cannot substitute for IL-2 in supporting Treg homeostasis ( Figure 5B) is consistent with previous observations that IL-21 is unable to substitute for IL-2 in driving Treg proliferation. [31][32][33] The significance of this lack of redundancy is that cytokines that alter IL-2 availability probably have a marked impact on Treg homeostasis. In this respect, it has recently been shown that IL-27 can negatively regulate the Treg population by down-regulating Tconv IL-2 production.…”

Section: Discussionmentioning

confidence: 99%

IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis

Attridge

Wang

Wardzinski

et al. 2012

Blood

119

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IntroductionAlthough regulation is essential for homeostatic control of the immune system, it also presents a barrier to effective tumor surveillance. Professional immune regulation is orchestrated by T cells expressing the transcription factor Foxp3, which fixes a genetic program that imparts suppressive function. The majority of Foxp3-expressing regulatory T cells appear to arise in the thymus and represent, in the main, a remarkably stable population committed to providing life-long immune regulation. 1 Regulatory T cells (Tregs) can call on a wide range of different mechanisms to exert suppressive activity, including pathways involving IL-10, TGF-␤, and CTLA4.In recent years, it has become apparent that the ability of Tregs to elicit effective suppression can be modified, not just by the ratio of suppressors to target cells, but also by the local cytokine environment. Multiple cytokines have reported to interfere with Treg suppression, including 2,3 TNF,3,[4][5][6][7]4,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]7 This raises the possibility that the way in which T cells differentiate may dictate the extent to which a given T-cell response may be regulated. Consistent with this notion, it has been shown that human Th17 clones are significantly less susceptible to Treg suppression than those exhibiting a Th1 or Th2 phenotype. 8 Understanding the rules that govern professional immune regulation has important implications for our ability to alter the magnitude of immune responses therapeutically, for example, to augment antitumor immunity or diminish autoimmunity. In this study, we have focused on the cytokine IL-21, which we and others have previously shown can counteract Treg suppression in vitro and in vivo. 6,7 We have explored the mechanism underlying the capacity of IL-21 to alter Treg suppression and have pinpointed which cell population needs to receive IL-21 signals to permit this effect. We find that IL-21 signaling to Tregs does not impair their suppressive capacity, but instead IL-21 signaling to conventional T cells is responsible for the abrogation of suppression. Our work reveals a novel feedback loop by which IL-21 impacts on Treg homeostasis by down-regulating IL-2 production from conventional T cells. Thus, in addition to inhibiting de novo Treg differentiation, an affect that has been well documented for IL-21, 9-11 this cytokine also negatively regulates the homeostasis of natural Tregs. Methods Mice DO11.10 TCR transgenic and BALB/c mice were purchased from The Jackson Laboratory. IL-21R Ϫ/Ϫ mice were provided by M.K. Rat insulin promoter (RIP)-mOVA mice on a BALB/c background expressing a membrane-bound form of OVA under the control of the RIP (from line 296-1B) were a gift from W. Heath (Walter and Eliza Hall Institute, Melbourne, Australia). DO11.10 mice and RIP-mOVA were crossed as previously described. 12 Mice were housed at the University of Birmingham Biomedical Services Unit and used according to Home Office and institutional guidelines under Home Office Project L...

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“…[30][31][32] Longitudinal monitoring of the CD8 T cells compartment will be needed to document the differentiation from naive to TEMRA cells. Before transplantation, an increase of TEMRA CD8 T cells and a decrease of naive CD8 T cells were associated with a lower risk of acute rejection.…”

Section: Cd28mentioning

confidence: 99%

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Yap

Boeffard

Clave

et al. 2014

Journal of the American Society of Nephrology

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Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vb repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8 + T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vb diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA + CCR7 2 CD27 2 CD28 2 ) CD8 + T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8 + T cells to secrete TNF-a and IFN-g. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8 + T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8 + T cells may improve the early identification of at-risk patients.

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The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells

Cited by 83 publications

References 52 publications

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

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