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Interleukin-15 (IL-15) is generally considered to be a regulator of T cell homeostasis because it works with other common gamma-chain cytokines like IL-2 and IL-7 to control the maintenance of naive and memory T cell populations. However, recent reports highlight new roles for IL-15 during the primary immune responses that involve promoting the survival of antigen-specific CD8+ T cells. These findings illuminate a previously unanticipated role for IL-15 in the generation and resolution of the effector CD8+ T cell response to pathogens.
IL-15 plays a pivotal role in T-cell activation and effector functions, including T cell proliferation , interferon-γ and tumor necrosis factor-α production [2,3], chemokine production , and cytotoxicity . In combination with other common gamma-chain cytokines, IL-15 also influences memory T cell homeostasis through the regulation of memory T cell numbers [6-8]. In this context, IL-15 drives the generation of antigen-specific memory T cells , promotes the survival of memory CD8+ T cells , and stimulates the homeostatic proliferation of memory phenotype CD8+ T cells [10-12]. Recent publications have described new roles for IL-15 in primary immune responses, where it provides a survival signal to effector CD8+ T cells during primary responses to pathogens [13,14].
Recently, Sanjabi et al.  demonstrated that transforming growth factor-βTGF-β and IL-15 have opposing effects on the survival of the short-lived effector T cells (defined on the basis of KLRG1 [killer cell lectin-like receptor G1] and CD127 expression). Using a model system of Listeria monocytogenes infection, the authors demonstrated that TGF-β promoted apoptosis of effector CD8+ T cells whereas IL-15 promoted their survival. The opposing effects of TGF-β and IL-15 were not a result of direct inhibition of signaling in the respective signaling pathways; rather, the differential survival appeared to result from the competing effects of these pathways on the anti-apoptosis molecule Bcl-2 (B-cell lymphoma 2). Importantly, these data supported a role for IL-15 in promoting the survival of effector T cells during the contraction phase of the T-cell response to infection.
This concept was extended by McGill et al. , who revealed a role for IL-15 in promoting the survival of antigen-specific CD8+ T cells in the lung after influenza virus infection. Using a dendritic cell (DC) depletion/reconstitution model, their previous work had demonstrated that influenza-specific CD8+ T cell responses in the lung depended on T-cell interactions with pulmonary DCs . When pulmonary DCs were depleted using clodronate-liposomes, antigen-specific CD8+ T cell responses were decreased, and the virus was not cleared as efficiently. The blunting of the CD8+ T-cell response was not due to reduced proliferation of T cells in the absence of DC signals, as DC depletion did not significantly alter the proliferation of antigen-specific CD8+ T cells responding to the infection. Instead, it appeared that the pulmonary DCs were promoting the survival of the antigen-specific T cells in the lung environment. This enhanced CD8+ T-cell survival was dependent on trans-presentation of IL-15/IL-15 receptor (IL-15R) complexes by pulmonary DCs, as blocking IL-15 or IL-15R on DCs resulted in increased CD8+ T-cell apoptosis in the lung. Together, these data support a two-hit model for promoting effective CD8+ T cell responses: a first hit in the lymph node that primes T-cell proliferation and migration to infected tissue, and a second hit that provides a survival signal to the effector T cells.
While IL-15 has been best-appreciated for its contributions to memory T cell homeostasis, these new findings highlight the importance of IL-15 in promoting the survival of antigen-specific CD8+ T cells during primary responses to infection and suggest several areas for further investigation. First, the location of the DC-T-cell interaction that promotes the survival of the CD8+ T cells needs to be determined. One possibility is that IL-15 trans-presentation by DCs takes place in inducible bronchus-associated lymphoid tissue that develops in the lungs after infection . Alternatively, the DC-T-cell interactions could take place in the lung-draining lymph node, as the pulmonary DC subsets continue to migrate to the lung-draining lymph node through day 9 post-infection . Second, the importance of IL-15 for the survival of memory T cell populations during a secondary pathogen challenge needs to be examined [18,19]. Finally, the contribution of IL-15 trans-presentation to the survival of CD4+ T cells during the primary immune response to pathogens needs to be determined. In this regard, IL-15 promotes the activation of CD4+ T cells – including their cytokine production , CD154 expression , proliferation , and the maintenance of memory populations  – yet the effect of IL-15 on CD4+ T-cell survival during primary immune responses is unknown.
Manipulating T cell survival via the IL-15 pathway offers the potential for the development of novel disease therapies. One such therapeutic approach was recently reported by Wang et al. , who alleviated joint inflammation in a model of arthritis by targeting toxins to IL-15R-expressing cells. This report revealed the potential for elimination of immunopathogenic T cells and offers a possible therapeutic pathway to treat T-cell-mediated diseases like multiple sclerosis or type I diabetes. Alternatively, the anti-apoptotic effects of IL-15 could also be utilized to enhance survival of effector T cells. Toward this end, Hoyos et al.  engineered tumor-specific T cells with an IL-15 construct, which enhanced T-cell survival and resulted in improved anti-tumor effects. Together, these studies reveal the potential for therapies targeting the IL-15 pathway in the treatment of disease and reinforce a role for IL-15 in promoting the survival of effector CD8+ T cells during the immune response.
Work performed in the senior author's laboratory was supported by National Institutes of Health grants AI67967, AI76499, and T32 AI49823.
The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/2/67
The authors declare that they have no competing interests.