Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4<sup>+</sup>and CD8<sup>+</sup>T Cells In Vivo

Moniuszko, Marcin; Fry, Terry J.; Tsai, Wen-Po; Morre, Michel; Assouline, Brigitte; Cortez, Pierre; Lewis, Mark G.; Cairns, Scott; Mackall, Crystal L.; Franchini, Genoveffa

doi:10.1128/jvi.78.18.9740-9749.2004

Cited by 70 publications

(72 citation statements)

References 32 publications

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“…Studies of IL-7 administration to uninfected and SIV-infected macaques have demonstrated a proliferative effect on CD4 ϩ and CD8 ϩ T cells expressing both memory and naïve phenotypes (27,28,38). Analogous results were obtained more recently in human cancer patients (39), as well as in HIV-1-infected individuals (M. Lederman, personal communication).…”

Section: Discussionsupporting

confidence: 60%

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals

Vassena

Proschan

Fauci

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis has been suggested as one of the major mechanisms of CD4 ؉ T cell depletion during the course of HIV type 1 (HIV-1) infection. Here, we show that interleukin 7 (IL-7), a nonredundant cytokine that plays essential roles in the generation and homeostasis of the T cell compartment of the immune system, exerts strong antiapoptotic effects ex vivo on both CD4 ؉ and CD8 ؉ T cells derived from HIV-1-infected subjects. The level of IL-7-mediated reduction of apoptosis was inversely correlated with the number of circulating CD4 ؉ T cells, indicating a higher sensitivity to IL-7 effects in patients with more advanced disease. The antiapoptotic effect of IL-7 was uncoupled from the induction of cellular proliferation or endogenous HIV-1 replication. These results provide a further rationale for consideration of IL-7 as an agent of immune reconstitution in HIV-1 infection.T lymphocytes ͉ immunodeficiency ͉ immune reconstitution ͉ programmed cell death ͉ cytokines

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Section: Discussionsupporting

confidence: 60%

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals

Vassena

Proschan

Fauci

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-7 maintains survival and homeostatic proliferation of naive and memory T cells in vivo (5)(6)(7)(8)(9)(10). In vitro, however, it has been reported that naive T cells do not proliferate in response to IL-7 (63-65), whereas memory T cells have been reported to slowly cycle (Ref.…”

Section: Discussionmentioning

confidence: 99%

IL-7 Induces Myelopoiesis and Erythropoiesis

Aiello

Keller

Klarmann

et al. 2007

The Journal of Immunology

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IL-7 administration to mice was previously reported to increase the mobilization of progenitor cells from marrow to peripheral sites. We now report that IL-7 increases the number of mature myeloid and monocytic cells in spleen and peripheral blood. This effect required T cells, and we show that IL-7 treatment in vivo induced GM-CSF and IL-3 production by T cells with memory phenotype. However, additional myelopoietic cytokines were shown to be involved because mice deficient in both GM-CSF and IL-3 also responded to IL-7 with increased myelopoiesis. Candidate cytokines included IFN-γ and Flt3 ligand, which were also produced in response to IL-7. Because IFN-γ-deficient mice also increased myelopoiesis, it was suggested that IL-7 induced production of redundant myelopoietic cytokines. In support of this hypothesis, we found that the supernatant from IL-7-treated, purified T cells contained myelopoietic activity that required a combination of Abs against GM-CSF, IL-3, and anti-Flt3 ligand to achieve maximum neutralization. IL-7 administration increased the number of splenic erythroid cells in either normal, Rag1 or GM-CSF-IL-3-deficient mice, suggesting that IL-7 might directly act on erythroid progenitors. In support of this theory, we detected a percentage of TER-119+ erythroid cells that expressed the IL-7Rα-chain and common γ-chain. Bone marrow cells expressing IL-7R and B220 generated erythroid colonies in vitro in response to IL-7, erythropoietin, and stem cell factor. This study demonstrates that IL-7 can promote nonlymphoid hemopoiesis and production of cytokines active in the host defense system in vivo, supporting its possible clinical utility.

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“…We interpret the above results to reveal the operation of a homeostatic mechanism that leads to increased cycling in the N T cell pool as the pool shrinks, perhaps as a consequence of increased availability of cytokines that regulate survival and cycling of N T cells (24). For example, IL-7 is believed to be the main regulator of N T cell turnover, and its administration to monkeys has been shown to increase N T cell proliferation (28). Based on our recent findings (19,29,30), the reduction in naïve T cell representation and diversity resulting from a mechanism of this kind would have the potential to adversely affect the induction of protective immunity.…”

Section: Discussionmentioning

confidence: 99%

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

Čičin‐Šain¹,

Messaoudi²,

Park

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

123

124

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The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G1-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.aging ͉ CD8 ͉ homeostasis T he immune system undergoes dramatic age-related changes in both structure and function. Of these, the best investigated and the most pronounced are the changes affecting aging T cells. Age-related changes were seen in T cell subset representation and T cell diversity in humans (1-3) and experimental animals (4, 5) and have been associated with higher mortality in the aging humans (6, 7). Moreover, impaired T cell activation has been documented in senescent rodent and human T cells (8)(9)(10)(11). Although the molecular lesions in T cell activation have been thoroughly studied, the picture of the age-related dysregulation of T cell populations is still emerging.Optimal protection against new or evolving pathogens requires a reserve of naïve T cells. However, naïve T cell production is reduced in old age because of the involution of the thymus. The maintenance of the naïve T cell compartment is further challenged by the lifelong consumption of naïve cells that respond to acute and persistent infections and become memory T cells. With age, the balance between naïve and antigenselected memory cells changes in favor of the latter, reducing the diversity of T cell receptors (TCRs). In fact, the aging naïve T cell population is reduced in both relative and absolute terms, suggesting that homeostatic mechanisms that maintain the size and the clonal diversity of the T cell repertoire progressively break down (12)(13)(14).T cells can also be replenished by extrathymic mechanisms, which rely on homeostatic proliferation in the absenc...

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Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4⁺and CD8⁺T Cells In Vivo

Cited by 70 publications

References 32 publications

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals

IL-7 Induces Myelopoiesis and Erythropoiesis

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

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Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4+and CD8+T Cells In Vivo

Cited by 70 publications

References 32 publications

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+and CD8+T cells from HIV-1-infected individuals

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+and CD8+T cells from HIV-1-infected individuals

IL-7 Induces Myelopoiesis and Erythropoiesis

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

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Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4⁺and CD8⁺T Cells In Vivo

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4⁺and CD8⁺T cells from HIV-1-infected individuals