Abramson AL. Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human papillomavirus-6 and -11. APMIS 2010; 118: 455-470. Recurrent respiratory papillomatosis (RRP) is a rare disease of the larynx caused by infection with human papillomaviruses (HPV) -6 or -11, associated with significant morbidity and on occasion mortality. Here we summarize our current understanding of the permissive adaptive and innate responses made by patients with RRP that support chronic HPV infection and prevent immune clearance of these viruses. Furthermore, we provide new evidence of T H 2-like polarization in papillomas and blood of patients with RRP, restricted CD4 and CD8 Vb repertoires, the effect of HPV-11 early protein E6 on T-cell alloreactivity, enriched Langerhans cell presence in papillomas, and evidence that natural killer cells are dysfunctional in RRP. We review the immunogenetic mechanisms that regulate the dysfunctional responses made by patients with RRP in response to HPV infection of the upper airway. In addition, we are identifying T-cell epitopes on HPV-11 early proteins, in the context of human leukocyte antigen (HLA) class II alleles enriched in RRP that should help generate a therapeutic vaccine. Taken together, RRP is a complex, multigene disease manifesting as a tissue and HPV-specific, immune deficiency that prevents effective clearance and ⁄ or control of HPV-6 and -11 infection.

Purpose Respiratory papillomas, caused by human papillomaviruses types 6 and 11 (HPV6/11), are premalignant lesions with potential for malignant conversion. The cytokine and chemokine micromilieu of papillomas is TH2-like with a marked absence of IFN-γ expression. To illuminate why patients with recurrent respiratory papillomatosis (RRP) fail to effectively control their disease, we further investigated the suppressive cellular microenvironment in papillomas. Experimental Design CD4+CD25+CD127low/−Foxp3+ Tregs, and CD4+CD25−CD127low/−Foxp3− T-cells within papillomas were characterized and isolated. Their suppressor function was measured by inhibition of PBMC proliferation. Expression of PD-1, CD69, and Helios was identified on these T-cells. PD-L1, PD-L2, CCL17, and CCL22 mRNA was also identified in papillomas. by QPCR. Results Functional Tregs were markedly enriched in papillomas and strongly inhibited anti-CD3 and anti-CD28 antibody activated PBMC proliferation. The natural Treg marker Helios was reduced on Tregs from papillomas, indicating that the majority of Tregs in papillomas are adaptive. The majority of the papilloma-derived CD4+ T-cells expressed the CD4+CD25−CD127low/−Foxp3−PD1+CD69+ phenotype and failed to suppress PBMC proliferation, suggesting that they are chronically activated and exhausted. The Treg-attracting chemokine CCL22 was equally expressed by all laryngeal tissues examined. However CCL17 was robustly expressed by papillomas compared to unaffected laryngeal tissues from RRP patients and individuals without RRP. PD-L1 was elevated in papillomas compared to control laryngeal tissues. Conclusions Papilloma CD4+ T-cells are enriched with functional Tregs, and the adaptive Helios− Treg fraction was increased within the TH2-like papilloma micromilieu. CD4+CD25−CD127low/−Foxp3− T-cells failed to suppress PBMC proliferation and may be exhausted. The PD-1/PDL-1 pathway may represent an additional immunosuppressive mechanism that contributes to defective HPV6/11 clearance in RRP.