IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

Saout, Cecile Le; Luckey, Megan A.; Villarino, Alejandro V.; Smith, Mindy; Hasley, Rebecca B.; Myers, Timothy G.; Imamichi, Hiromi; Park, Jung Hyun; O’Shea, John J.; Lane, H. Clifford; Catálfamo, Marta

doi:10.1172/jci.insight.96228

Cited by 18 publications

(15 citation statements)

References 52 publications

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“…Conversely, those that were not expected, such as pSTAT signaling from LPS and PMA/ionomycin-stimulated cells, were not observed (fig. S5) ( 22 , 23 ). These alignments to the existing signaling knowledge further supported the strength of our experimental approach.…”

Section: Resultsmentioning

confidence: 99%

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

et al. 2020

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Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer’s disease (AD) or Parkinson’s disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCγ2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCγ2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.

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Section: Resultsmentioning

confidence: 99%

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

et al. 2020

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“…Both absolute CD4 + T cell counts and CD127 + CD4 + memory T cell frequencies increase to levels observed in uninfected individuals (105), though CD127 expression levels on CD4 + T cells remain lower (106). With restoration of absolute CD4 + T cell levels, IL-7 in the serum decreases and IL-7 mediated STAT-5 phosphorylation, which is elevated in memory CD4 + T cells in untreated infection (107), is normalized (108). Functionally, memory CD4 + T cells exhibit improved IL-2 release, HIV-1-specific CD4 + T cell responses increase in frequency (100, 109) and CD4 + T cell responses to vaccination improve (101).…”

Section: Art Restores the Cd4+ T Cell Memory Transitionmentioning

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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“…Instead, repopulation of the peripheral T cell population is predominantly driven by lymphopenia-induced proliferation, mediated by the increased availability of γc cytokines, such as IL-7 and IL-15. Lymphopenia-induced proliferation favors expansion of CD8 + memory T cells, because CD8 + memory T cells express higher levels of a component of the IL-15 receptor (CD122) ( 11 ) and CD4 + T cell homeostatic expansion is limited by IL-7-dependent STAT-1 activation ( 12 ). More recently, signaling from γc cytokines has been seen to drive metabolic remodeling in T cells in mouse models of aging, inflammation, and lymphopenia ( 13 – 15 ), but the impact of lymphopenia-inducing therapies on T cell metabolism in aged humans has not been defined.…”

Section: Introductionmentioning

confidence: 99%

Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells

et al. 2020

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New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4 + and CD8 + T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4 + T cells, and an increase in effector memory T cells and PD1-expressing CD4 + T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.

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IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

Cited by 18 publications

References 52 publications

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

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

Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells

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