IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

Beltra, Jean-Christophe; Bourbonnais, Sara; Bédard, Nathalie; Charpentier, Tania; Boulangé, Moana; Michaud, Eva; Boufaied, Inès; Bruneau, Julie; Shoukry, Naglaa H.; Lamarre, Alain; Decaluwe, Hélène

doi:10.1073/pnas.1604256113

Cited by 52 publications

(34 citation statements)

References 45 publications

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“…To determine whether the FV-specific PD-1/SIRPα double-positive CD8 + T cells from chronically infected mice comprised a subset of cells with a distinct phenotype, the expression of additional markers was examined by flow cytometry. The PD-1 + SIRPα + CD8 + T cells from chronically infected mice also expressed high levels of the co-inhibitory receptors Tim3 and Lag3, CD95 (Fas), which leads to apoptosis upon ligand binding, and IL-2Rβ chain (CD122), which helps drive a PD-1 hi phenotype 36 (Fig. 3a–d).…”

Section: Resultsmentioning

confidence: 99%

A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

Myers¹,

Tal

Dulgeroff

et al. 2019

Nat Commun

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Prolonged exposure of CD8+ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+ T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα+ CD8+ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα+ cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8+ T cell-killing in vivo. SIRPα+ CD8+ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+ T cells during chronic infection expands the cytotoxic subset of SIRPα+ CD8+ T cells.

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Section: Resultsmentioning

confidence: 99%

A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

Myers¹,

Tal

Dulgeroff

et al. 2019

Nat Commun

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“…The in vivo persistence and activation of adoptively transferred T cells is usually maintained by IL-2 infusion, but with IL-15 as exogenous supplement or as transgene expressed, preclinical mouse studies demonstrated an enhanced antitumor capacity of CD8+T cells compared with IL-2 [83]. Recent studies have shown that IL-2 and IL-15 both triggered CD8+ T cell exhaustion by similarly inducing the expression of inhibitory receptor in vivo, particularly 2B4 and TIM-3, and selective abrogation of their common IL-2Rβchain could retain the inhibitory receptor induction [84]. In breast cancer, IL-15 provoked higher proliferation and IFNγ production of tumor-infiltrating CD8+ T cells than IL-2, and these strong but short-lived response could be diminished by the subsequently upregulated TIM-3 [85].…”

Section: Immunomodulation Of T and Nk Cells In The Tumor Microenvironmentioning

confidence: 99%

Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

Yang

Lundqvist

2020

Cancers

104

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The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. While IL-2 expands regulatory T cells and CD4+ helper T cells, IL-15 supports the development of central memory T cells and NK cells. Recent data have provided evidence that IL-2 and IL-15 differ in their ability to activate T and NK cells to resist various forms of immune suppression. The diverse roles of these two cytokines have on immune cells lead to critical therapeutic implications for cancer treatment. In this review, we discuss the distinct roles of IL-2 and IL-15 in activating various functions in T and NK cells with a particular focus on the signals that participate in the resistance of tumor-derived immune suppressive factors. Furthermore, we summarize current clinical applications of IL-2 and IL-15 in metastatic malignancies, either as monotherapy or in combination with other agents, and highlight the future trends for research on these cytokine-based immunotherapies.

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“…CD122 (IL-2Rβ), a receptor shared by IL-2 and IL-15, becomes upregulated as exhaustion develops which correlates with the emergence of impaired functionality and increased PD-1 expression. Deletion of CD122 lessens exhaustion and increases functionality, implying that the integration of IL-2 and IL-15 signals influences the ontogeny and fates of exhausted CD8 T cells [ 191 ]. Although the expression of CD122 is prolonged on LCMV-specific CD8 T cells during chronic LCMV infection when compared to parallel populations in acutely infects hosts, expression on exhausted cells does eventually subside [ 59 , 191 ].…”

Section: Extrinsic Drivers Of T Cell Exhaustionmentioning

confidence: 99%

Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus

Kahan

Zajac

2019

Viruses

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Lymphocytic choriomeningitis virus (LCMV) is a paradigm-forming experimental system with a remarkable track record of contributing to the discovery of many of the fundamental concepts of modern immunology. The ability of LCMV to establish a chronic infection in immunocompetent adult mice was instrumental for identifying T cell exhaustion and this system has been invaluable for uncovering the complexity, regulators, and consequences of this state. These findings have been directly relevant for understanding why ineffective T cell responses commonly arise during many chronic infections including HIV and HCV, as well as during tumor outgrowth. The principal feature of exhausted T cells is the inability to elaborate the array of effector functions necessary to contain the underlying infection or tumor. Using LCMV to determine how to prevent and reverse T cell exhaustion has highlighted the potential of checkpoint blockade therapies, most notably PD-1 inhibition strategies, for improving cellular immunity under conditions of antigen persistence. Here, we discuss the discovery, properties, and regulators of exhausted T cells and highlight how LCMV has been at the forefront of advancing our understanding of these ineffective responses.

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IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

Cited by 52 publications

References 45 publications

A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus

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