Lipsker Dan, Ziylan Umit, Spehner Danièle, Proamer Fabienne, Bausinger Huguette, Jeannin Pascale, Salamero Jean, Bohbot Alain, Cazenave Jean-Pierre, Drillien Robert, Delneste Yves, Hanau Daniel, de la Salle Henri
INSERM, Equipe Propre 99-08, Etablissement Français du Sang-Alsace, 10 rue Spielmann, BP 36, F-67065 Strasbourg Cedex, France.
Eur J Immunol. 2002 Feb;32(2):322-32. doi: 10.1002/1521-4141(200202)32:2<322::AID-IMMU322>3.0.CO;2-0.
Priming of CTL by means of heat shock proteins (hsp) is dependent on antigen-presenting cells (APC), which present the hsp-associated peptides, via their cell surface MHC class I molecules, toCD8(+) T cells. It has not yet been established how human (hu) hsp70 interacts with the major (hu)APC, the dendritic cells (DC). Here we show that (hu)hsp70 is specifically internalized intoCD14(-), Toll-like receptor 4(-) monocyte-derived (hu)DC by receptor-mediated endocytosis. We further demonstrate that (hu)hsp70 and (hu)hsp60 share the same receptors on (hu)monocyte-derived DC. Both molecules as well as MHC class I molecules are spontaneously internalized and reach the MHC class II-enriched compartments. Finally, freshly isolated (hu) epidermal Langerhans cells (LC), the DC of the skin, as well as CD34(+)-derived LC do not bind hsp60 or hsp70. Given the likely importance of the internalization of hsp70 by APC in the induction of the immune responses, the finding that hsp60 and hsp70 are internalized through the same receptor(s) may explain why microbial hsp60 represents a major T cell antigen. This may rationalize the use of microbial hsp60 to prime immune responses against microbes. The lack of hsp60/70 receptors on epidermal LC raises the crucial question as to whether absence of priming of the skin and mucosal immune systems by hsp-polypeptide complexes could account for some tissue-specific diseases. This work also points to a potential advantage of using monocyte-derived DC in human immunotherapeutic applications of hsp60/70.
通过热休克蛋白（hsp）启动细胞毒性T淋巴细胞（CTL）依赖于抗原呈递细胞（APC），后者通过其细胞表面的MHC I类分子将与hsp相关的肽呈递给CD8(+) T细胞。人类（hu）hsp70如何与主要的人类APC即树突状细胞（DC）相互作用尚未明确。在此我们表明，（hu）hsp70通过受体介导的内吞作用被特异性内化到CD14(-)、Toll样受体4(-)单核细胞衍生的（hu）DC中。我们进一步证明，（hu）hsp70和（hu）hsp60在（hu）单核细胞衍生的DC上具有相同的受体。这两种分子以及MHC I类分子都会自发内化并到达富含MHC II类分子的区室。最后，新鲜分离的人类表皮朗格汉斯细胞（LC），即皮肤的DC，以及CD34(+)衍生的LC不结合hsp60或hsp70。鉴于APC内化hsp70在诱导免疫反应中可能具有的重要性，hsp60和hsp70通过相同受体内化这一发现或许可以解释为什么微生物hsp60是主要的T细胞抗原。这可能使利用微生物hsp60启动针对微生物的免疫反应具有合理性。表皮LC上缺乏hsp60/70受体引发了一个关键问题，即hsp - 多肽复合物缺乏对皮肤和黏膜免疫系统的启动作用是否可以解释某些组织特异性疾病。这项工作还指出了在hsp60/70的人类免疫治疗应用中使用单核细胞衍生DC的潜在优势。
