Homeostasis of Naive and Memory CD4+ T Cells: IL-2 and IL-7 Differentially Regulate the Balance Between Proliferation and Fas-Mediated Apoptosis

Jaleco, Sara; Swainson, Louise; Dardalhon, Valérie; Burjanadze, Maryam; Kinet, Sandrina; Taylor, Naomi

doi:10.4049/jimmunol.171.1.61

Cited by 88 publications

(77 citation statements)

References 65 publications

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“…More recently it has been established that a disruption of T cell homeostasis through the persistent stimulation of naïve cells, pushing them along the path of differentiation, is a contributing factor to HIV disease progression [2, 8,9]. Under normal conditions, when there is a reduction of T cell numbers in the periphery, levels of IL-7 increase to send survival signals via the IL-7R to promote antigen independent, or homeostatic proliferation to rebalance T cell numbers [16,44]. In lymphopenic HIV-infected individuals, there is an elevated level of IL-7 caused by the homeostatic response to T cell depletion [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Although many correlates have been identified that may influence the rate of HIV progression, including immune activation, and the disruption of T cell homeostasis, a complete understanding of the mechanisms of CD4 + T cell decline remains elusive [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Cytokines that signal through the common gamma chain, such as IL-2, IL-4, IL-7, and IL-15, are some of the main mediators of T cell homeostasis [15][16][17][18][19][20][21]. This study focused on one of these cytokine receptors, the IL-7R.…”

Section: Introductionmentioning

confidence: 99%

“…Signaling via the IL-7R is essential in the developmental process of lymphoid cells [22] and is key in the homeostatic regulation of the entire T cell compartment. The maintenance of all CD4 + and CD8 + naïve, and more importantly memory T cell subsets is regulated via many complex signals, one of which being that received through the IL-7R [16,18,[23][24][25][26][27][28][29][30][31]. In fact, this receptor is up-regulated on primary effector cells destined to become long-term memory cells [32].…”

Section: Introductionmentioning

confidence: 99%

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IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

et al. 2006

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Many factors can influence the rate of HIV disease progression, including those that maintain T cell homeostasis. One key homeostatic regulator is the IL‐7 receptor (IL‐7R). Previous studies have shown IL‐7R expression levels decrease in HIV infection, but effects on memory subtypes, CD4+ T cells, and cell function have not been explored. The present study examined the expression of the IL‐7Rα chain on naïve and memory T lymphocyte subsets of both HIV‐positive and HIV‐negative individuals from Nairobi, Kenya to assess the role of IL‐7Rα in HIV disease. Expression of IL‐7Rα was significantly reduced in all CD4+ and CD8+ T cell subsets in HIV‐positive individuals. This reduction was further enhanced in those with advanced HIV progression. Expression of IL‐7Rα was inversely correlated to immune activation, and apoptosis, and was positively correlated with CD4 count in both bivariate and multivariate analysis. Expression of IL‐7Rα did not correlate with HIV viral loads, indicating the elevated immune activation seen in HIV‐infected individuals may be impacting expression of IL‐7Rα, independent of viral loads. Signaling via the IL‐7R is essential for T cell homeostasis and maintenance of T cell memory. Reduction of this receptor may contribute to the homeostatic disruption seen in HIV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

et al. 2006

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“…IL-2 controls T-cell clonal expansion and contraction, and promotes lymphocyte differentiation. IL-2 and IL-15 can also support memory cell division and have been used in combination with Ag-driven stimulation, for the expansion of CTL [24][25][26][27][28][29]. IL-7 regulates peripheral T-cell homeostasis, and contributes to the generation and long-term survival of both CD4 1 and CD8 1 memory T lymphocytes in vivo [30,31].…”

mentioning

confidence: 99%

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Caserta

Alessi²,

Basso³

et al. 2010

Eur J Immunol

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It is well established that tumours hinder both natural and vaccine-induced tumourspecific CD4 1 T-cell responses. Adoptive T-cell therapy has the potential to circumvent functional tolerance and enhance anti-tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8 1 T cells are currently available, data on tumour-specific CD4 1 T cells remain scarce. We report here that CD4 1 T cells sensitized to tumour-associated Ag in vivo, proliferate in vitro in response to IL-7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory-like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumoursensitized T cells among other memory and naive lymphocytes following exposure to IL-7. Also IL-2, previously used to expand anti-tumour CTL, promotes tumour-specific CD4 1 T-cell accumulation. However, IL-7 is superior to IL-2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4 1 T cells to confer therapeutic efficacy upon transplantation in tumour-bearing hosts. Together our data support a unique role for IL-7 in retrieving memory-like CD4 1 T cells suitable for adoptive T-cell therapy.Key words: Adoptive T-cell therapy . Cytokines . T helper cells . Tumour immunology Supporting Information available online IntroductionAdoptive cell therapy (ACT) with tumour-specific CD8 1 T lymphocytes has become one of the most promising approaches in cancer therapy. Rosenberg et al. first demonstrated the possibility to expand tumour-specific cytotoxic CD8 1 lymphocytes (CTL) from tumour lesions in high doses of IL-2 [1]. These authors later showed that the state of lymphocyte differentiation, induced in the presence of common g-chain receptor cytokines, is critical for therapeutic efficacy [2,3]. In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic 470viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL. Thus, CD4 1 T cells have not been widely exploited in ACT as well as the properties (i.e. homing potential, functionality, and survival) that CD4 1 T cells might require for successful applications in ACT are much less known than in the case for CD8 1 CTL.A large, still not definitive, amount of ...

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“…The increased concentration of IL-7 found in T cell-depleted individuals is considered to be a homeostatic response to T cell depletion, which may accelerate thymic output and promote peripheral T cell survival and proliferation (22,29,30). In addition to the extensive data on T cell maintenance by IL-7, it has also been suggested that IL-7 might participate in the up-regulation of Fas expression on naive T lymphocytes (34,35). Another study described IL-7 as a stimulator of Fas-induced apoptosis in T cell cultures infected with HIV-1 (36).…”

mentioning

confidence: 99%

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Fluur

Milito

Fry

et al. 2007

The Journal of Immunology

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IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

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Homeostasis of Naive and Memory CD4+ T Cells: IL-2 and IL-7 Differentially Regulate the Balance Between Proliferation and Fas-Mediated Apoptosis

Cited by 88 publications

References 65 publications

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

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Homeostasis of Naive and Memory CD4+ T Cells: IL-2 and IL-7 Differentially Regulate the Balance Between Proliferation and Fas-Mediated Apoptosis

Cited by 88 publications

References 65 publications

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Contact Info

Product

Resources

About

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells