Interleukin‐7 Receptor Signaling Is Deficient in CD4<sup>+</sup>T Cells from HIV‐Infected Persons and Is Inversely Associated with Aging

Bazdar, Douglas A.; Kalinowska, Magdalena; Sieg, Scott F.

doi:10.1086/597210

Cited by 48 publications

(42 citation statements)

References 50 publications

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“…T cell responsiveness to IL-7 depends largely on the surface expression of IL-7Ra (CD127), which is a hallmark of naive T cells, as well as IL-7 intracellular signal transduction pathway (47). HIV infection is known to perturb IL-7 signaling in T cells (7,(48)(49)(50). Moreover, alterations in IL-7 expression, signaling, and survival responses have been reported in effector-memory cells from elderly (51).…”

Section: Discussionmentioning

confidence: 99%

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Sauce¹,

Larsen²,

Fastenackels³

et al. 2012

The Journal of Immunology

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Reduced thymopoiesis and continuous mobilization of naive T cells into the effector–memory pool can lead to severe alterations of the naive T cell compartment. However, maintenance of the naive T cell population is essential to mount effective immune responses. Evidence of homeostatic regulation of naive T cells is currently debated in animal models. In humans, the situation remains unresolved, in particular with advanced age. In this study, we analyzed the CD4+ and CD8+ naive T cell compartments from elderly, young adults thymectomized during early childhood, and HIV-1–infected patients, which are characterized by T lymphocytopenia. We show a direct association between increased turnover and decreased frequency of naive T cells. Moreover, the IL-7–induced pathway was fully functional in naive T cells from elderly and young adults thymectomized during early childhood, who are characterized by elevated IL-7 plasma levels. Our findings support the establishment of homeostatic regulation of naive T cell proliferation in humans. This regulation is particularly active in lymphopenic hosts, such as elderly and thymectomized patients.

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Section: Discussionmentioning

confidence: 99%

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Sauce¹,

Larsen²,

Fastenackels³

et al. 2012

The Journal of Immunology

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“…Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9)(10)(11)(12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13)(14)(15)(16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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“…ϩ T cells of patients with active HIV replication (9). On the other hand, we observed signs of STAT5 hyperactivation, as indicated by (i) an increased level of pSTAT5 induction per cell within the population of CD4 ϩ T cells that still responded to IL-7 stimulation, (ii) a higher level of pSTAT5 induction for a given level of CD127 expression in CD4 ϩ T cells of viremic patients than in those of healthy donors, and (iii) increased STAT5 phosphorylation levels at the baseline in both the naive and the memory CD4 ϩ T-cell compartments of viremic patients.…”

Section: Il-7 Is the Key Cytokine That Regulates The Homeostasis Of Pmentioning

confidence: 99%

Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway

Juffroy

Bugault

Lambotte

et al. 2010

J Virol

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Interleukin‐7 Receptor Signaling Is Deficient in CD4⁺T Cells from HIV‐Infected Persons and Is Inversely Associated with Aging

Cited by 48 publications

References 50 publications

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway

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Interleukin‐7 Receptor Signaling Is Deficient in CD4+T Cells from HIV‐Infected Persons and Is Inversely Associated with Aging

Cited by 48 publications

References 50 publications

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway

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Interleukin‐7 Receptor Signaling Is Deficient in CD4⁺T Cells from HIV‐Infected Persons and Is Inversely Associated with Aging