IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

Belarif, Lyssia; Mary, Caroline; Jacquemont, Lola; Le, Hoa; Danger, Richard; Hervouet, Jérémy; Minault, David; Thépénier, Virginie; Nerrière-Daguin, Véronique; Nguyen, Elisabeth; Pengam, Sabrina; Largy, Eric; Delobel, Arnaud; Martinet, Bernard; Bas‐Bernardet, Stéphanie Le; Brouard, Sophie; Soulillou, Jean‐Paul; Degauque, Nicolas; Blancho, Gilles; Vanhove, Bernard; Poirier, Nicolas

doi:10.1038/s41467-018-06804-y

Cited by 56 publications

(56 citation statements)

References 69 publications

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“…Human infants with IL-7Rα mutations have severe T cell lymphopenia necessitating bone marrow transplantation (82). In contrast to most studies performed in rodent models where IL-7R blockade also induces broad lymphodepletion (21), administration of high doses of anti-IL-7Rα antagonistic mAb in baboons (83), cynomolgus monkey (84), or marmosets (85) did not induce lymphopenia or a significant decrease in peripheral T lymphocyte numbers. Similarly, early clinical results from phase I trials with 2 different antagonist anti-IL-7Rα mAbs, in healthy volunteers (GSK2618960; NCT02293161, ClinicalTrials.gov) or in type 1 diabetic adult patients (PF-06342674; NCT02038764), did not demonstrate induction of lymphopenia (86).…”

Section: Discussionmentioning

confidence: 98%

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

Belarif

Danger

Kermarrec

et al. 2019

Journal of Clinical Investigation

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101

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Section: Discussionmentioning

confidence: 98%

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

Belarif

Danger

Kermarrec

et al. 2019

Journal of Clinical Investigation

Self Cite

101

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“…In humans, mutations in the IL7Rα result in severe combined immunodeficiency (SCID) which is associated with the absence of T cells and normal numbers, nevertheless inactive, B cells 52 . Accordingly, targeting IL7Rα using specific antibodies may also affect T cells 53 and lead to immunodeficiency in patients. However, a recent study showed that treating healthy subjects with anti-human IL7R antibody was well tolerated and did not result in obvious alterations in immune cell populations and inflammatory cytokine profiles 54 .…”

Section: Discussionmentioning

confidence: 99%

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

et al. 2020

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Ph + acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph + ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph + ALL. Targeting this platform with anti-IL7R antibody eliminates Ph + ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

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“…Monoclonal antibodies (MAb) that antagonize the IL-7Rα (111) are in investigation for treatment of a range of autoimmune diseases and inflammatory conditions, including diabetes (112), multiple sclerosis, rheumatoid arthritis (113, 114), and inflammatory bowel disease (115). The aim of these approaches is to suppress aberrant memory CD4 + T cell responses (116).…”

Section: Therapeutic Implications Of Art-mediated Restoration Of Cd4+mentioning

confidence: 99%

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

et al. 2019

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Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4 + T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4 + T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4 + T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4 + T cells from naïve cells, it is essential for the further transition of effectors to memory CD4 + T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4 + T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127 + CD4 + memory T cells increases, indicating restoration of effector to memory transition in CD4 + T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4 + T cells transition to long-lived, CD127 + CD4 + T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4 + T cell memory formation will limit the generation of long-lived HIV-infected CD4 + T cells and reduce the overall size of the stable HIV-1 reservoir.

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IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

Cited by 56 publications

References 69 publications

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

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