Immune suppression in premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression.
Immune suppression in premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression.
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DOI：
10.1158/1078-0432.ccr-11-2941
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发表时间：
2012-04-01
期刊：
影响因子：
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通讯作者：
Bonagura VR
中科院分区：
文献类型：
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作者：
Hatam LJ;Devoti JA;Rosenthal DW;Lam F;Abramson AL;Steinberg BM;Bonagura VR
呼吸道乳头状瘤是由人乳头状瘤病毒6型和11型（HPV 6/11）引起的，是具有恶变潜力的癌前病变。乳头状瘤的细胞因子和趋化因子微环境是TH 2样的，IFN-γ表达明显缺失。为了阐明复发性呼吸道乳头状瘤病（RRP）患者无法有效控制疾病的原因，我们进一步研究了乳头状瘤中的抑制性细胞微环境。对乳头状瘤内的CD 4 + CD 25 + CD 127低/− Foxp 3 + T细胞和CD 4 + CD 25 − CD 127低/− Foxp 3 − T细胞进行了表征和分离。通过抑制PBMC增殖来测量它们的抑制功能。在这些T细胞上鉴定了PD-1、CD 69和Helios的表达。PD-L1、PD-L2、CCL 17和CCL 22 mRNA也在乳头状瘤中鉴定。通过QPCR。乳头状瘤中功能性T淋巴细胞明显富集，并强烈抑制抗CD 3和抗CD 28抗体激活的PBMC增殖。天然Treg标记Helios在来自乳头状瘤的TcM上减少，表明乳头状瘤中的大多数TcM是适应性的。大多数乳头状瘤来源的CD 4 + T细胞表达CD 4 + CD 25 − CD 127 low/− Foxp 3 − PD 1 + CD 69+表型，并且不能抑制PBMC增殖，这表明它们被慢性激活和耗尽。Treg-吸引趋化因子CCL 22在所有检查的喉组织中同等表达。然而，与来自RRP患者和没有RRP的个体的未受影响的喉组织相比，CCL 17在乳头状瘤中强烈表达。与对照喉组织相比，乳头状瘤中PD-L1升高。乳头状瘤CD 4 + T细胞富含功能性T细胞，并且在TH 2样乳头状瘤微环境中自适应Helios− Treg分数增加。CD 4 + CD 25 − CD 127 low/− Foxp 3 − T细胞不能抑制PBMC增殖，并可能耗尽。PD-1/PDL-1通路可能是导致RRP中HPV 6/11清除缺陷的另一种免疫抑制机制。
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. 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. 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. 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.