IL-7 induces proliferation, variable cytokine-producing ability and IL-2 responsiveness in naive CD4+ T-cells from human cord blood

Fukui, Tetsuya; Katamura, Kenji; Abe, Nobutaka; Kiyomasu, Takahiro; Iio, Jun; Ueno, Hideki; Mayumi, Mitsufumi; Furusho, Kenshi

doi:10.1016/s0165-2478(97)00093-x

Cited by 37 publications

(39 citation statements)

References 39 publications

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“…This is in contrast to previous in vitro reports demonstrating that IL-7 induces several activation markers, suggesting a state of activation (3,8,11,26). In addition, our results demonstrate that 2 days of IL-7 treatment does not alter the expression of the activation/memory markers CD44 or CD62L (27-29) on either T cell subset, suggesting that IL-7 does not activate naive cells or induce them to become memory cells.…”

Section: Discussioncontrasting

confidence: 99%

“…Moreover, administration of IL-7 in vivo does not induce alterations in most activation and memory markers examined. This is in contrast to in vitro models that have shown an up-regulation of several activation molecules (3,8,11), thereby demonstrating that in this regard, previously reported in vitro results are not representative of what occurs in vivo. Finally, our results demonstrate that the increase in T cell numbers after IL-7 administration is attributable at least in part to the ability of IL-7 to induce additional T cells to enter cell cycle.…”

contrasting

confidence: 85%

“…In addition, reports indicate that human T cells may proliferate more robustly to IL-7 than mouse T cells, and some results suggest that the proliferation induced by IL-7 is dependent on the presence of APC (2-4, 8, 9). Although IL-7 does not appear to switch T cells from CD45RA to CD45RO (10), upregulation of activation markers such as CD25, CD98, CD71, CD11a, and CD40 ligand has been reported in vitro (3,8,11). In addition, less mature T cells (such as those from human cord blood) appear to proliferate more vigorously to IL-7 than do T cells from adults (12).…”

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confidence: 99%

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IL-7 Administration Alters the CD4:CD8 Ratio, Increases T Cell Numbers, and Increases T Cell Function in the Absence of Activation

Geiselhart¹,

Humphries²,

Gregorio

et al. 2001

The Journal of Immunology

130

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IL-7 is vital for the development of the immune system and profoundly enhances the function of mature T cells. Chronic administration of IL-7 to mice markedly increases T cell numbers, especially CD8+ T cells, and enhances T cell functional potential. However, the mechanism by which these effects occur remains unclear. This report demonstrates that only 2 days of IL-7 treatment is needed for maximal enhancement of T cell function, as measured by proliferation, with a 6- to 12-fold increase in the proportion of CD4+ and CD8+ T cells in cell cycle by 18 h of ex vivo stimulation. Moreover, a 2-day administration of IL-7 in vivo increases basal proliferation by 4- and 14-fold in CD4+ and CD8+ T cells, respectively. These effects occur in the absence of cytokine production, increases in most activation markers, and changes in memory markers. This enhanced basal proliferation is the basis for the increase in T cell numbers in that IL-7 induces an additional 60% and 85% of resting CD4+ and CD8+ T cells, respectively, to enter cell cycle in mice given IL-7 for 7 days. These results demonstrate that in vivo administration of IL-7 increases T cell numbers and functional potential via a homeostatic, nonactivating process. These findings may suggest a unique clinical niche for IL-7 in that IL-7 therapy may increase T cell numbers and enhance responses to specific antigenic targets while avoiding a general, nonspecific activation of the T cell population.

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Section: Discussioncontrasting

confidence: 99%

contrasting

confidence: 85%

mentioning

confidence: 99%

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IL-7 Administration Alters the CD4:CD8 Ratio, Increases T Cell Numbers, and Increases T Cell Function in the Absence of Activation

Geiselhart¹,

Humphries²,

Gregorio

et al. 2001

The Journal of Immunology

130

View full text Add to dashboard Cite

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“…Ki-67 expression peaked on day 7 (13%) and was followed by a rapid decline (data not shown). Intracellular Ki-67 staining demonstrated the proliferation of IL-7-treated resting CD4 + T lymphocytes, in agreement with previous studies (31)(32)(33)(34)(35)(36). Figure 2B illustrates the cell activation efficiency when treated with PHA and then IL-2.…”

Section: Il-7-mediated Viral Replication Is In Part Dependent On Actisupporting

confidence: 90%

IL-7 is a potent and proviral strain–specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART

Wang

Xu²,

Sullivan³

et al. 2005

J. Clin. Invest.

122

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The persistence of HIV-1 in virally suppressed infected individuals on highly active antiretroviral therapy (HAART) remains a major therapeutic problem. The use of cytokines has been envisioned as an additional therapeutic strategy to stimulate latent proviruses in these individuals. Immune activation therapy using IL-2 has shown some promise. In the present study, we found that IL-7 was significantly more effective at enhancing HIV-1 proviral reactivation than either IL-2 alone or IL-2 combined with phytohemagglutinin (PHA) in CD8-depleted PBMCs. IL-7 also showed a positive trend for inducing proviral reactivation from resting CD4 + T lymphocytes from HIV-1-infected patients on suppressive HAART. Moreover, the phylogenetic analyses of viral envelope gp120 genes from induced viruses indicated that distinct proviral quasispecies had been activated by IL-7, as compared with those activated by the PHA/IL-2 treatment. These studies thus demonstrate that different activators of proviral latency may perturb and potentially deplete only selected, specific portions of the proviral archive in virally suppressed individuals. The known immunomodulatory effects of IL-7 could be combined with its ability to stimulate HIV-1 replication from resting CD4 + T lymphocytes, in addition to other moieties, to potentially deplete HIV-1 reservoirs and lead to the rational design of immuneantiretroviral approaches.

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“…18,19 IL-7 treatment can also induce IL-2 receptor (CD25) expression on naive T cells, rendering them more responsive to the IL-2-mediated effects. 20 In vivo IL-7 treatment was shown to successfully induce immune reconstitution following bone marrow transplantation in the mouse model, as measured by IL-7-mediated enhancement in the proliferation of immature thymocytes and improved survival after challenge with influenza virus. 18 IL-7 has also been shown to increase a marker of de novo T-cell synthesis known as T-cell receptor excision circles (TRECs) in thymic explant models, 21 possibly by inducing intrathymic T-cell receptor rearrangement 22,23 or by enhancing the survival of early thymocyte progenitors.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1

Steffens

Managlia

Landay

et al. 2002

Blood

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Although human immunodeficiency virus (HIV) gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), Mtropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA ؉ CD45RO ؊ , CD45RA ؉ CD62L ؉ , and CD45RO ؊ CD27 ؉ CD95 low ) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA ؉ CD45RO ؊ expression to define naive T cells in this study. We demonstrate that although untreated or IL-2-treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This upregulation was between 8-and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients. IntroductionCD4 ϩ primed/memory T cells constitute the main target for productive human immunodeficiency virus (HIV) infection. [1][2][3] Whether HIV productively infects naive T cells in vivo is still controversial. 4-9 Naive T cells were shown to harbor replicationcompetent HIV, 7,10 but are not an active site of HIV replication in the absence of mitogen stimulation. 11 Even in studies demonstrating HIV infection of naive T cells, further analysis of integrated HIV indicated that HIV DNA did not always integrate into the genome. 5,10 Infected naive T cells, nonetheless, have been identified in HIV-seropositive individuals, 7,10 but it is unclear if such in vivo naive T cells were once primed cells that reverted to a naive phenotype 12,13 or are truly naive T cells that are infected in vivo. In the simian immunodeficiency virus (SIV) model, SIV RNA was detected by in situ hybridization in naive T cells, suggesting that these cells may serve as an additional reservoir for HIV. 14 Collectively, the consensus is that naive T cells, either in vivo or in vitro, do not support HIV productive infection mainly because these cells exist in a quiescent stage, a concept that is being challenged. The association between productive HIV replication and cell turnover is presumably due to the higher level of deoxyribonucleotides present for reverse transcription 15 during cell division or due to t...

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IL-7 induces proliferation, variable cytokine-producing ability and IL-2 responsiveness in naive CD4+ T-cells from human cord blood

Cited by 37 publications

References 39 publications

IL-7 Administration Alters the CD4:CD8 Ratio, Increases T Cell Numbers, and Increases T Cell Function in the Absence of Activation

IL-7 Administration Alters the CD4:CD8 Ratio, Increases T Cell Numbers, and Increases T Cell Function in the Absence of Activation

IL-7 is a potent and proviral strain–specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART

Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1

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