A slew of recent basic immunology papers have identified the cytokine interleukin-21 (IL-21) as playing a key role in the maintenance of antiviral T cell responses. One cross-sectional study in HIV infection has reported that IL-21 levels are lower in HIV-positive individuals compared to their seronegative counterparts, but no other data has been presented. A paper just published in the Journal of Immunology now offers a more comprehensive assessment of the impact of HIV infection on IL-21, showing that among individuals followed longitudinally, levels of the cytokine decline progressively and correlate with peripheral blood CD4 T cell counts. The researchers, led by Alexandre Iannello from the University of Montreal, also show that IL-21 levels do not appear to completely normalize after initiation of antiretroviral therapy. Analyses of HIV-specific CD4 T cells suggest a specific deficit in the ability of this population to make IL-21 that may be a consequence of their preferential infection with HIV.
The authors conclude that IL-21 may deserve evaluation as a potential immunotherapy for HIV infection. The patent on the therapeutic use of IL-21 is owned by a Seattle-based company called Zymogenetics who are currently evaluating it as a cancer treatment, but studies in HIV or other chronic viral infections have not yet been initiated. Interestingly, another recent paper published in the Journal of Leukocyte Biology (abstract also included below) suggests that IL-21 might have a role in promoting the expansion of functional CD28+ CD8 T cells over senescent CD28- CD8 T cells, which could conceivably add to the rationale for exploring its therapeutic potential in HIV.
Published online November 30, 2009
The Journal of Immunology, 2009, doi:10.4049/jimmunol.0901967
Alexandre Iannello,* Mohamed-Rachid Boulassel, Suzanne Samarani,* Olfa Debbeche,* Cécile Tremblay, Emil Toma, Jean-Pierre Routy, and Ali Ahmad*
*Laboratory of Innate Immunity, Centre Hospitalier Universitaire Sainte-Justine Research Center, Department of Microbiology and Immunology, and Division of Infectious Diseases, Centre hospitalier de l’Université de Montréal Hotel-Dieu, University of Montreal; and McGill University Health Center, McGill University, Montreal, Canada
IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4+ T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4+ T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4+ T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4+ T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21–producing HIV-specific, but not human CMV-specific, Ag-experienced CD4+ T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4+ T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.
J Leukoc Biol. 2009 Oct 1. [Epub ahead of print]
Nguyen H, Weng NP.
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28(+) CD8 memory T cells over their CD28(-) counterparts, as CD28(+) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28(+) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28(+) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.