Key Points Single-cell heterogeneity, rather than lineage reprogramming, explains the remarkable complexity and functional diversity of human Tregs. Altered homeostasis of Treg subpopulations in patients developing acute graft-versus-host disease.

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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