Mechanism of ultraviolet radiation induced immune tolerance

人类和小鼠一样，长期暴露于紫外线辐射B（UVB，290-320 nm）会损害宿主 免疫反应以及诱导突变细胞。肿瘤只有在有突变细胞的时候才会发生 在免疫抑制的环境中。事实上，接受器官移植的人， 免疫抑制药物会大大增加患皮肤癌的风险（高达100倍）， 肿瘤的发展表现得更具侵略性。已知UVB诱导的DNA损伤是一种 触发免疫耐受细胞衰老是一种阻止转化和生长的保护机制 DNA损伤的细胞。衰老细胞可以产生许多炎症介质，这种现象称为 衰老相关分泌表型（SASP）。SASP招募并激活免疫细胞， 清除DNA受损细胞，这是免疫监视的关键机制。然而，SASP也有 在免疫抑制和肿瘤促进中的作用。已知UVB诱导细胞衰老和SASP。 然而，尚不清楚SASP是否是UVB诱导耐受的机制。我们的研究表明， 衰老细胞的耗竭减少UVB诱导的SASP并抑制耐受性。结果显示， 以前未认识到的UVB诱导耐受机制。此外，我们发现CD 11b +/PD-L1+ UVB使细胞数量显著增加，而衰老细胞的减少使细胞数量减少。重要的是， 用抗PD-L1抗体治疗抑制UVB诱导的耐受性。据我们所知，这是第一个 证据表明PD-1/PD-L1检查点抑制剂在UVB诱导的耐受性中起作用。我们的假设是 UVB诱导细胞衰老和SASP是UVB诱导耐受性抗原的新机制 提呈细胞（APC）、Treg细胞和免疫耐受。目标1将研究消耗的机制， 衰老细胞的衰老抑制了皮肤中UVB诱导的耐受性和免疫抑制环境。我们将 检查衰老细胞的耗竭是否抑制Treg细胞并增强效应T细胞。进一步研究 将确定SASP介导的骨髓细胞的募集和刺激是否是UVB的机制 诱导的致耐受性APC和耐受性。我们还将研究UVB诱导的SASP是否与 人类的宽容目的2：探讨IL-17在UVB诱导SASP和肿瘤发生中的作用。我们 将确定IL-17是否是UVB诱导SASP的组分和上游调节剂，并检查 IL-17调节SASP的分子机制。进一步的研究将检查阻断IL-17是否 降低小鼠对光致癌作用的敏感性。目的3将确定CD 11b +/PD-L1+ 细胞是特异性致耐受性APC，用于诱导Treg细胞和耐受性，以及是否阻断PD- 1/PD-L1逆转UVB耐受小鼠中已建立的免疫耐受。进一步的研究将审查是否 阻断PD-1/PD-L1可抑制光致癌作用， 增强UVB诱导的皮肤肿瘤的免疫治疗的功效。

In humans, as in mice, chronic exposure to ultraviolet radiation B (UVB, 290-320 nm) impairs host immune responses in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. In fact, organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of skin cancers and the tumors that do develop behave more aggressively. It has been known that UVB induced DNA damage is a trigger for immune tolerance. Cell senescence is a protective mechanism to prevent transformation and growth of cells with DNA damage. Senescent cells can produce many inflammatory mediators, a phenomenon called senescence associated secretory phenotype (SASP). SASP recruits and activates immune cells to eliminate DNA damaged cells, which is a critical mechanism of immune surveillance. However, SASP also has roles in immunosuppression and tumor promotion. It is known that UVB induces cell senescence and SASP. However, it is not known whether SASP is a mechanism for UVB induced tolerance. Our studies show that depletion of senescent cells diminishes UVB induced SASP and inhibits tolerance. The result reveals a previously unrecognized mechanism for UVB induced tolerance. Further, we have found that CD11b+/PD-L1+ cells are significantly increased by UVB whereas they are reduced by depletion of senescent cells. Importantly, treatment with anti-PD-L1 antibodies inhibits UVB induced tolerance. To our best knowledge, this is the first evidence that PD-1/PD-L1 checkpoint inhibitor has a role in UVB induced tolerance. Our hypothesis is that UVB induced cell senescence and SASP are a novel mechanism for UVB induced tolerogenic antigen presenting cells (APC), Treg cells, and immune tolerance. Aim 1 will examine mechanisms by which depletion of senescent cells inhibits UVB induced tolerance and immune suppressive environments in skin. We will examine whether depletion of senescent cells inhibits Treg cells and enhances effector T cells. Further studies will determine whether SASP mediated recruitment and stimulation of myeloid cells is a mechanism for UVB induced tolerogenic APC and tolerance. We will also examine whether UVB induced SASP is associated with tolerance in humans. Aim 2 will determine a novel role of IL-17 in UVB induced SASP and carcinogenesis. We will determine whether IL-17 is a component and an upstream regulator of UVB induced SASP and examine molecular mechanisms by which IL-17 regulates SASP. Further studies will examine whether blockade of IL-17 diminishes the susceptibility of mice to photocarcinogenesis. Aim 3 will determine whether CD11b+/PD-L1+ cells are specific tolerogenic APC for the induction of Treg cells and tolerance and whether blockade of PD- 1/PD-L1 reverses established immune tolerance in UVB-tolerized mice. Further studies will examine whether blockade of PD-1/PD-L1 inhibits photocarcinogenesis and whether a combination with neutralizing IL-17 enhances the efficacy of immunotherapy for UVB induced skin tumors.