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A Chronic Need for IL-21 EDITORIAL
  Science 19 June 2009:
Vol. 324. no. 5934, pp. 1525 - 1526
DOI: 10.1126/science.1176487
Lisa D. S. Johnson and Stephen C. Jameson
Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Chronic viral infections provoke a war of attrition between cytotoxic T cells (the CD8+ subclass) of the immune system and infected host cells. Although the CD8+ T cell response gradually whittles away at the viral load, the cells progressively become "exhausted" and lose function during a chronic infection (1). This exhaustion becomes more severe in the absence of helper CD4+ T cells, potentially leading to viral persistence and loss of virus-specific CD8+ T cells (1, 2). But how do CD4+ cells help? Three reports in this issue, by Elsaesser et al. on page 1569 (3), Yi et al. on page 1572 (4), and Fršhlich et al. on page 1576 (5), suggest an unexpected role for a specific cytokine produced by CD4+ T cells called interleukin-21 (IL-21) in controlling chronic viral infections.
IL-21 is produced by multiple CD4+ T cell subsets, prominently T helper 17 (TH17) cells, follicular helper T cells, and natural killer T cells (6, 7). The cytokine enhances differentiation of some of these subsets, but other immune cells, including B, natural killer, and CD8+ T cells, also respond to IL-21. The IL-21 receptor (IL-21R) belongs to the {gamma}C family of cytokine receptors (which includes receptors for IL-2, -7 and -15), and IL-21 can cooperate with other members of that group to enhance CD8+ T cell responses (8, 9). This lays the groundwork for considering whether CD4+ cell "help" for CD8+ T cell responses involves IL-21 as an intermediary.
The new reports show that in mice, IL-21 is produced by CD4+ T cells responding to chronic lymphocytic choriomeningitis virus (LCMV) infection. As the infection persists, these T cells increase IL-21 production (while decreasing IL-2 production) (3, 4) (see the figure). To test the relevance of this response, IL-21- or IL-21R-deficient mice were chronically infected with LCMV. Surprisingly, the studies found that both types of mice were more susceptible than normal mice to chronic infection, and had more dramatic exhaustion of LCMV-specific CD8+ T cells. Furthermore, IL-21- and IL-21R-deficient mice could not overcome chronic infection compared to normal mice that were infected. By contrast, the magnitude of the CD4+ T cell response was normal [or even enhanced (3)] in the IL-21- and IL-21R-deficient mice. Antibody production by B cells to LCMV was mildly impaired in IL-21- and IL-21R-deficient animals (IL-21 simulates B cell function) (6, 7), but antibody is not thought critical for controlling chronic LCMV infection.
Because the sustained presence of viral antigen during chronic infection reinforces CD8+T cell exhaustion, IL-21 might enhance viral clearance by affecting other cells types (e.g., CD4+ T cells). This might also relieve CD8+ T cell exhaustion. The new studies addressed this issue by assessing the function of IL-21R-deficient CD8+ T cells in normal recipient mice. CD8+ T cells lacking IL-21R had impaired self-maintenance, suggesting an autonomous requirement for IL-21 sensitivity. Whether IL-21 also acts on other immune cell types to resolve chronic LCMV infection remains to be determined.
But is IL-21 the critical element that allows CD4+ T cells to help CD8+ T cells combat chronic viral infection? Yi et al. report that in response to injected IL-21, CD4+-deficient mice with a chronic LCMV infection showed enhanced numbers and function of CD8+ T cells and reduced viral titers. Although none of the new studies conclusively show that IL-21 produced by CD4+ T cells is essential for helping CD8+ T cells during chronic LCMV infection, the prominence of CD4+ T cells as a source for IL-21 is highly suggestive. IL-21 shows promise in tumor treatments (another scenario in which the immune system is subject to chronic antigen exposure) (6, 10), and its therapeutic potential is appealing. At the same time, the capacity of IL-21 to enhance the CD8+ T cell response may come at a cost: Treating chronic LCMV-infected CD4+-deficient animals with IL-21 led to severe sickness (4). Hence, prospective therapeutic use of IL-21 will need to be finely tuned.
CD4+ T cell help is also important for the CD8+ T cell response to various acute infections (2). In such responses, lack of CD4+ help (or lack of IL-2 sensitivity) typically has minimal impact on CD8+ T cell priming, but leads to a failure of memory CD8+ T cells to mount a response to subsequent infection by the same pathogen (2). The current reports find no effect of IL-21 or IL-21R deficiency on the primary CD8+T cell responses to various acute infections (3-5), and in one study, memory CD8+ T cell responses to LCMV were intact (5). Such data strongly suggest that IL-21 is a key element of CD4+ T cell help in CD8+ T cell responses to chronic but not acute infections. Furthermore, the elevated and sustained production of IL-21 (but not IL-2) in CD4+ T cells from chronically infected animals contrasts with the sustained capacity for IL-2 (but not IL-21) synthesis by CD4+ T cells following acute infection (3). Thus, the basis by which CD4+ T cells help the CD8+ T cell responses may change depending on the nature of the infection. IL-21 appears to induce a unique differentiation pathway in activated CD8+ T cells (6, 10, 11), potentially equipping them to better clear virus during a chronic infection. Whether the IL-21-producing CD4+ T cells also function as follicular helper T cells or TH17 cells during chronic viral infection is unclear [although Fršhlich et al. argue against TH17 involvement (5)]. Regardless, these studies suggest a key role for IL-21 in mediating CD4+ help when it's needed most.
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