Interleukin-7, but Not Thymic Stromal Lymphopoietin, Plays a Key Role in the T Cell Response to Influenza A Virus

Abstract

The immune response to viral infection is ideally rapid and specific, resulting in viral clearance and establishment of immune memory. Some viruses such as HIV can evade such responses leading to chronic infection, while others like Influenza A can elicit a severe inflammatory response with immune-related complications including death. Cytokines play a major role in shaping the appropriate outcomes to infection. While Interleukin-7 (IL-7) has a critical role in T and B cell development, treatment with IL-7 has recently been shown to aid the adaptive T cell response in clearance of chronic viral infection. In contrast, the IL-7-related cytokine thymic stromal lymphopoietin (TSLP) has a limited role in lymphocyte development but is important in the immune response to parasitic worms and allergens. The role for these cytokines in the immune response to an acute viral infection is unclear. IL-7 and TSLP share IL-7Rα as part of their heterodimeric receptors with the gamma common chain (γc) and TSLPR, respectively. We investigated the role of IL-7 and TSLP in the primary immune response to influenza A infection using hypomorphic IL-7Rα (IL-7Rα449F) and TSLPR−/− mice. We found that IL-7, but not TSLP, plays an important role in control of influenza A virus. We also showed that IL-7 signaling was necessary for the generation of a robust influenza A-specific CD4 and CD8 T cell response and that this requirement is intrinsic to CD8 T cells. These findings demonstrate a significant role for IL-7 during acute viral infection.

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

“…Our model suggests that CD4 + T cell expansion in cells undergoing LIP is regulated by an IL-7-dependent signaling composed by activation of STAT1 and STAT5, and this mechanism limits the expansion of the CD4 + T cell pool. The transcription of STAT1/IFN-associated genes may also reflect other potential properties of IL-7 (47,48). Recently, we have described that IL-7 can potentiate the responsiveness of T cells to type I IFNs by modulating the expression levels of STAT1 (37).…”

The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449

“…I nterleukin-7 is a critical cytokine for the development of B and T cells, the development of antiviral T cell responses and maintenance of memory T cells (1)(2)(3)(4). Thymic stromal lymphopoietin (TSLP) is a related cytokine important in Th2 responses and immunity at mucosal sites (5).…”

A Direct and Nonredundant Role for Thymic Stromal Lymphopoietin on Antiviral CD8 T Cell Responses in the Respiratory Mucosa

“…While it has been reported that TSLP-R −/− cells express lower levels of the inflammatory chemokine receptor CXCR3 (37), TSLP-R −/− OT-I cells were able to accumulate in the respiratory tract (Fig. 4), indicating to us that loss of TSLP did not impact migration to the mucosa.…”

“…Moreover, TSLP expression was also enhanced following infections with the respiratory pathogens Rhinovirus and Respiratory syncytial virus in human and rat airway epithelial cells, respectively (35). Recently, it has also been shown that infection with the highly pathogenic strain of influenza A virus, Puerto Rico/8 (PR8) can induce the production of TSLP mRNA in the lungs and trachea of mice (36), although data is conflicting as to whether or not this affects the anti-influenza CD8 T cell response, either directly or indirectly, and to what extent (36, 37). …”