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

Abstract

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...

Impact of HIV Infection and HAART Therapy on CD4 T Helper Cell Subset Expression and Function

“…On the other hand, excess Treg activity results in "over" suppression of immune responses resulting in too much immune suppression, leading to faster HIV progression and negative outcomes (Kinter, Horak et al, 2007). This point is also supported by a report showing that recombinant IL-2 treatment in a phase III trial actually enhanced Treg populations, possibly explaining why this treatment failed to elicit better clinical outcome (Weiss, Letimier et al, 2010). Treg depletion has been associated with an increase in immune activation (Eggena, Barugahare et al, 2005) and several important studies have demonstrated correlation of Treg proliferation and turnover with lower CD4 counts (Bi, Suzuki et al, 2009;Piconi, Trabattoni et al, 2010;Xing, Fu et al, 2010).…”

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

“…Accordingly, IL-2 therapy in lymphopenic patients leads to increases in regulatory-like CD4 T cell counts at the expense of the conventional T cell compartment, leading to altered responses to pathogens (46)(47)(48). Conversely, administration of IL-7 in humans induces expansion of naive and memory T cell subsets (49)(50)(51) and, in some clinical trials, a relative decrease in the percentage of regulatory CD4 + T cells was observed (52).…”

The split personality of regulatory T cells in HIV infection

“…Expanded Tregs suppressed proliferation of effector T cells in vitro, a result that may explain why these patients did not experience a clinical benefit despite sustained increases in CD4 counts. 59 In contrast to IL-2, recombinant IL-7 therapy was found to preferentially expand non-Treg cells resulting in a relative decrease of Treg within the total CD4 T-cell population. 60 The role of Treg should also be considered in therapeutic vaccine trials for HIV infection since Treg may prevent the vaccine-induced anti-HIV-1-specific polyfunctional responses.…”