IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection

Abstract

Rhinoviruses are the most common virus to infect man causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity however their function during rhinovirus infection in vivo is undefined. In RV infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expression of IL-15 and IL-15Rα which in turn were required for NK- and CD8+ T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9 and CXCL10 followed by recruitment of activated, IFN-γ expressing NK, CD8+ and CD4+ T cells. Treating infected IFNAR1−/− mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ and CXCL9 (but not CXCL10) expression also followed by NK-, CD8+- and CD4+-T cell recruitment and activation. We have demonstrated that type I IFN induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

Update on Human Rhinovirus and Coronavirus Infections

“…Following epithelial cell attachment and internalization, HRV infection results in cytokine expression, including type I and type III interferons (IFNs), interleukin (IL)-6, IL-11, IL-12, IL-15, and IL-1B. [28][29][30][31][32] Neutrophil recruitment results from release of growth factors and chemokines.…”

The role of airway epithelial cells and innate immune cells in chronic respiratory disease

“…The ILC1 population can include NK cells, which are probably more abundant in the lungs than ILC2s or ILC3s 136 . NK cell recruitment and activation is primarily mediated by epithelial cell release of IL-15, which increases in the nasal mucosa within a few days after HRV challenge 137 . The relevance of this response to post-viral airway disease is uncertain, but NK cell expression of NK group 2 member D (NKG2D; also known as KLRK1) and granzyme B was required for the allergic response to house dust mite extract in mice 138 .…”

In vivo experimental models of infection and disease

“…154 RV infection also stimulated IL-15 production and release into the airways, which is dependent on type I IFN production and stimulates activation of natural killer (NK) and CD8 1 T cell responses. 155 Treatment with an IL-15ÀIL-15Ra complex increased expression of IL-15, IL-15Rα, IFNγ, and CXCL9 and stimulated increased NK, CD8 1 , and CD4 1 T cell recruitment and activation. 155 CCL7 and IRF-7 are the most upregulated lung transcripts following RV-A1 infection.…”

“…155 Treatment with an IL-15ÀIL-15Ra complex increased expression of IL-15, IL-15Rα, IFNγ, and CXCL9 and stimulated increased NK, CD8 1 , and CD4 1 T cell recruitment and activation. 155 CCL7 and IRF-7 are the most upregulated lung transcripts following RV-A1 infection. 156 Blocking CCL7 or IRF-7 function reduced lung neutrophil and macrophage accumulation and IFN responses and blocking CCL7 also reduced AHR.…”