Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis.

Abstract

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1-like and/or Tc1-like adaptive response, thus resulting in the predominant TH2-like and/or Treg micromilieu present in papillomas.

• Authors: James DeVoti, Lynda Hatam, Alexandra Lucs, Ali Afzal, Allan Abramson, Bettie Steinberg, Vincent Bonagura
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 20 Pg. 372-80 (Aug 28 2014) ISSN: 1528-3658 [Electronic] England
• PMID: 24950037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CCL1 protein, human
• Chemokine CCL1
• IL36G protein, human
• Interleukin-1
• Interleukin-1beta

Topics

• Cells, Cultured
• Chemokine CCL1 (genetics, immunology)
• Human papillomavirus 11
• Humans
• Immunity, Innate
• Interleukin-1 (genetics, immunology)
• Interleukin-1beta (genetics, immunology)
• Keratinocytes (immunology, virology)
• Langerhans Cells (immunology)
• Larynx (immunology)
• Papillomavirus Infections (immunology)
• Respiratory Tract Infections (immunology)