Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients

Kovacs, Joseph A.; Lempicki, Richard A.; Sidorov, Igor A.; Adelsberger, Joseph W.; Sereti, Irini; Sachau, William; Kelly, Gerald D.; Metcalf, Julia A.; Davey, Richard T.; Falloon, Judith; Polis, Michael A.; Tavel, Jorge A.; Stevens, Randy; Lambert, Laurie; Hosack, Douglas A; Bosche, Marjorie; Issaq, Haleem J.; Fox, Stephen D.; Leitman, Susan F.; Baseler, Michael; Masur, Henry; Mascio, Michele Di; Dimitrov, Dimiter S.; Lane, H. Clifford

doi:10.1172/jci23196

Cited by 114 publications

(105 citation statements)

References 25 publications

(30 reference statements)

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“…Although isotope labeling studies in humans are typically restricted to blood, it has been reported that labeling kinetics in human T cells derived from blood and lymphoid tissues are comparable (29). Label incorporation in T cells derived from mouse peripheral lymph nodes and spleen was also similar (unpublished data).…”

Section: Discussionmentioning

confidence: 86%

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Vrisekoop

Braber

Boer

et al. 2008

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

198

327

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In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool. recent thymic emigrants ͉ T cell half-lives ͉ T cell production T he role of the thymus in HIV infection is still poorly understood (1, 2). On the one hand, thymic failure has been suggested to play a crucial role in CD4 T cell loss during HIV infection (3), and rapid thymic rebound has been proposed to be responsible for T cell reconstitution during anti-viral treatment (4). However, it has been argued that thymic output in adults might be too low to have a large impact on CD4 T cell depletion (5). In general, these issues are addressed with estimates of thymic output, naïve and memory T cell production rates, and life spans that are simply extrapolated from observations in mice, monkeys, and lymphopenic or irradiated humans (6-11).Naïve T cells are generally thought to turnover relatively slowly, but it has been suggested that, in mice, a considerable part of the naïve T cell pool consists of RTEs with relatively rapid turnover (9, 10, 12). In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al. (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15, 16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1, 2, 5), and, therefore, they fail to quantify thymic output in humans.Peripheral T cell proliferation might also contribute to the maintenance of the naïve T cell pool in human adults; however, it is unclear which fraction of these cells remains in the naïve T cell pool (17). The contribution of RTEs and peripheral T cell proliferation to the maintenance of the naïve T cell pool can only be determined by studying the fate of newly produced T cells. In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates ...

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Section: Discussionmentioning

confidence: 86%

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Vrisekoop

Braber

Boer

et al. 2008

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

198

327

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“…IL-2 and IL-7 administered to HIV-1-infected individuals was shown to enhance the frequency of CD4 + T cells (29,(54)(55)(56). In SIV-infected macaques, IL-15 failed to improve viral loads after a therapeutic SIV vaccine, and it had no effect on SIV-specific CD8 + function (57).…”

Section: Discussionmentioning

confidence: 99%

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Mujib

Jones

et al. 2012

The Journal of Immunology

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T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8+ and Th1 CD4+ T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3+ cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-γ and TNF-α. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4+ T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as γc cytokine stimulation with successive divisions. γc cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3+ primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or γc cytokines, likely through the PI3K pathway.

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“…In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1)(2)(3)(4)(5)(6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.…”

mentioning

confidence: 99%

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Weiss

Letimier

Carrière

et al. 2010

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

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HIV-1 infection is characterized by a progressive decline in CD4 + T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4 + counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4 + counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4 + T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4 + CD25 + T cell populations (CD4 + CD25 lo CD127 lo FOXP3 + and CD4 + CD25 hi CD127 lo FOXP3 hi ) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4 + CD25 + T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4 + CD25 hi FOXP3 + T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4 + T cells had a higher relative risk of clinical progression to AIDS. molecular profiling | immune-based therapy H IV infection is mainly associated with a progressive decrease in the number of CD4 + T lymphocytes and defective CD4-and CD8-specific T cell responses against HIV and other pathogens. Quantitative and qualitative CD4 T cell reconstitution following introduction of antiretroviral therapy (ART) in HIVinfected patients is often incomplete, leading one to evaluate the impact of immune-based therapy in combination with ART. In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1-6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.The clinical impact of IL-2 was evaluated in two long-run large phase III trials (SILCAAT and ESPRIT) involving almost 6,000 chronically HIV-1-infected patients. Results recently reported showed that, despite a sustained increase in CD4 + T cell counts, over a median follow-up of 7-8 years, IL-2-treated patients did not experience a better clinical outcome (7). These disappointing results have remained unexplained so far.In mice, IL-2 has been shown to be essential for the...

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Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients

Cited by 114 publications

References 25 publications

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

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Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients

Cited by 114 publications

References 25 publications

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

Contact Info

Product

Resources

About

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients