Flacher Vincent, Sparber Florian, Tripp Christoph H, Romani Nikolaus, Stoitzner Patrizia
Department of Dermatology and Venereology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
Cancer Immunol Immunother. 2009 Jul;58(7):1137-47. doi: 10.1007/s00262-008-0563-9. Epub 2008 Aug 2.
Langerhans cells, a subset of skin dendritic cells in the epidermis, survey peripheral tissue for invading pathogens. In recent functional studies it was proven that Langerhans cells can present exogenous antigen not merely on major histocompatibility complexes (MHC)-class II molecules to CD4+ T cells, but also on MHC-class I molecules to CD8+ T cells. Immune responses against topically applied antigen could be measured in skin-draining lymph nodes. Skin barrier disruption or co-application of adjuvants was required for maximal induction of T cell responses. Cytotoxic T cells induced by topically applied antigen inhibited tumor growth in vivo, thus underlining the potential of Langerhans cells for immunotherapy. Here we review recent work and report novel observations relating to the potential use of Langerhans cells for immunotherapy. We investigated the potential of epicutaneous immunization strategies in which resident skin dendritic cells are loaded with tumor antigen in situ. This contrasts with current clinical approaches, where dendritic cells generated from progenitors in blood are loaded with tumor antigen ex vivo before injection into cancer patients. In the current study, we applied either fluorescently labeled protein antigen or targeting antibodies against DEC-205/CD205 and langerin/CD207 topically onto barrier-disrupted skin and examined antigen capture and transport by Langerhans cells. Protein antigen could be detected in Langerhans cells in situ, and they were the main skin dendritic cell subset transporting antigen during emigration from skin explants. Potent in vivo proliferative responses of CD4+ and CD8+ T cells were measured after epicutaneous immunization with low amounts of protein antigen. Targeting antibodies were mainly transported by langerin+ migratory dendritic cells of which the majority represented migratory Langerhans cells and a smaller subset the new langerin+ dermal dendritic cell population located in the upper dermis. The preferential capture of topically applied antigen by Langerhans cells and their ability to induce potent CD4+ and CD8+ T cell responses emphasizes their potential for epicutaneous immunization strategies.
朗格汉斯细胞是表皮中皮肤树突状细胞的一个亚群，负责监测外周组织是否有入侵的病原体。在最近的功能研究中证实，朗格汉斯细胞不仅可以将外源性抗原呈递在主要组织相容性复合体（MHC）II类分子上以呈递给CD4 + T细胞，还可以呈递在MHC I类分子上以呈递给CD8 + T细胞。在引流皮肤的淋巴结中可以检测到针对局部应用抗原的免疫反应。为了最大程度地诱导T细胞反应，需要破坏皮肤屏障或联合应用佐剂。局部应用抗原诱导的细胞毒性T细胞在体内抑制肿瘤生长，从而突出了朗格汉斯细胞在免疫治疗中的潜力。在此，我们综述了最近的研究工作，并报告了与朗格汉斯细胞在免疫治疗中的潜在用途相关的新观察结果。我们研究了表皮免疫策略的潜力，即在原位使驻留的皮肤树突状细胞负载肿瘤抗原。这与当前的临床方法形成对比，当前临床方法是在将血液中的祖细胞产生的树突状细胞在体外负载肿瘤抗原后再注射到癌症患者体内。在当前研究中，我们将荧光标记的蛋白质抗原或针对DEC - 205/CD205和朗格蛋白/CD207的靶向抗体局部应用于屏障破坏的皮肤上，并检查朗格汉斯细胞对抗原的捕获和转运。可以在原位朗格汉斯细胞中检测到蛋白质抗原，并且它们是从皮肤外植体迁移过程中运输抗原的主要皮肤树突状细胞亚群。用少量蛋白质抗原进行表皮免疫后，测量到了CD4 +和CD8 + T细胞在体内的强效增殖反应。靶向抗体主要由朗格蛋白阳性的迁移性树突状细胞运输，其中大多数代表迁移性朗格汉斯细胞，较小的一部分是位于真皮上层的新的朗格蛋白阳性真皮树突状细胞群体。朗格汉斯细胞对局部应用抗原的优先捕获及其诱导强效CD4 +和CD8 + T细胞反应的能力强调了它们在表皮免疫策略中的潜力。
