Grabbe S, Bruvers S, Granstein R D
Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
J Invest Dermatol. 1994 Jan;102(1):67-73. doi: 10.1111/1523-1747.ep12371734.
Cutaneous I-A+ Langerhans cells are the principal antigen-presenting cells within the epidermis, capable of both initiating and eliciting CD4-dependent immune reactions. We recently demonstrated that epidermal Langerhans cells can present tumor-associated antigens and thus may be important in cutaneous tumor immunity. Despite the ability of Langerhans cells to present tumor antigens, they generally fail to induce protective tumor immunity against growing tumors in situ. We therefore investigated whether locally produced cytokines may be able to down-regulate the presentation of tumor-associated antigens and alloantigen by epidermal antigen-presenting cells in primed as well as in unprimed systems in vivo and in vitro. Naive syngeneic mice could be successfully immunized against the spindle cell tumor S1509a by injecting them with granulocyte-macrophage colony-stimulating factor-exposed and tumor-associated antigen-pulsed epidermal cells three times at weekly intervals. Co-incubation of epidermal cells in granulocyte-macrophage colony-stimulating factor and interleukin-1 alpha inhibited tumor-antigen presentation by epidermal antigen-presenting cells in this system and also inhibited alloantigen presentation in the primary mixed epidermal cell-lymphocyte reaction. Tumor necrosis factor-alpha appeared to be a significant mediator of the inhibitory effect of interleukin-1 alpha on the ability of epidermal antigen-presenting cells to induce protective tumor immunity, because addition of anti-tumor necrosis factor-alpha antibody abrogated the observed effect of interleukin-1 alpha. However, the effects of interleukin-1 alpha and tumor necrosis factor-alpha differed with regard to presentation of tumor-associated antigens by epidermal antigen-presenting cells in a primed system. Whereas incubation of epidermal cells in interleukin-1 alpha before or after tumor antigen pulse inhibited their ability to elicit a delayed-type hypersensitivity response against S1509a tumor-associated antigens in tumor-immune mice, culture in tumor necrosis factor-alpha significantly enhanced delayed-type hypersensitivity. Again, these in vivo data corresponded well to similar results obtained in vitro using the secondary mixed epidermal cell-lymphocyte reaction. Incubation of epidermal cells in transforming growth factor-beta, which has been shown to down-regulate T-cell-mediated immune responses in other systems, did not suppress tumor immunity in our assays. Thus, interleukin-1 alpha may be an important regulator of Langerhans cell antigen-presenting function, having effects that are partially mediated via interleukin-1 alpha-induced up-regulation of tumor necrosis factor-alpha secretion within the skin.
皮肤I-A+朗格汉斯细胞是表皮内主要的抗原呈递细胞，能够启动和引发CD4依赖性免疫反应。我们最近证明，表皮朗格汉斯细胞可以呈递肿瘤相关抗原，因此可能在皮肤肿瘤免疫中起重要作用。尽管朗格汉斯细胞有呈递肿瘤抗原的能力，但它们通常无法在原位诱导针对生长中肿瘤的保护性肿瘤免疫。因此，我们研究了局部产生的细胞因子是否能够在体内和体外的致敏及未致敏系统中，下调表皮抗原呈递细胞对肿瘤相关抗原和同种异体抗原的呈递。通过每周给同基因的未致敏小鼠注射三次粒细胞-巨噬细胞集落刺激因子处理过且负载肿瘤相关抗原的表皮细胞，可成功使其对梭形细胞瘤S1509a产生免疫。在该系统中，将表皮细胞与粒细胞-巨噬细胞集落刺激因子和白细胞介素-1α共同孵育，可抑制表皮抗原呈递细胞的肿瘤抗原呈递，也能抑制初次混合表皮细胞-淋巴细胞反应中的同种异体抗原呈递。肿瘤坏死因子-α似乎是白细胞介素-1α对表皮抗原呈递细胞诱导保护性肿瘤免疫能力产生抑制作用的重要介质，因为添加抗肿瘤坏死因子-α抗体可消除所观察到的白细胞介素-1α的作用。然而，在致敏系统中，白细胞介素-1α和肿瘤坏死因子-α对表皮抗原呈递细胞呈递肿瘤相关抗原的影响有所不同。在肿瘤免疫小鼠中，在肿瘤抗原脉冲之前或之后将表皮细胞置于白细胞介素-1α中孵育，会抑制它们对S1509a肿瘤相关抗原引发迟发型超敏反应的能力，而在肿瘤坏死因子-α中培养则显著增强迟发型超敏反应。同样，这些体内数据与使用二次混合表皮细胞-淋巴细胞反应在体外获得的类似结果非常吻合。在转化生长因子-β中孵育表皮细胞，在其他系统中已证明其可下调T细胞介导的免疫反应，但在我们的试验中并未抑制肿瘤免疫。因此，白细胞介素-1α可能是朗格汉斯细胞抗原呈递功能的重要调节因子，其作用部分是通过白细胞介素-1α诱导皮肤内肿瘤坏死因子-α分泌上调来介导的。
