do Nascimento de Freitas Deise, Gassen Rodrigo Benedetti, Fazolo Tiago, Souza Ana Paula Duarte de
Laboratório de Imunologia Clinica e Experimental; Centro Infant, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
Laboratório de Imunologia Clinica e Experimental; Centro Infant, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratório de Imunologia Celular e Molecular, PUCRS, Brazil.
Toxicol In Vitro. 2016 Oct;36:114-119. doi: 10.1016/j.tiv.2016.07.016. Epub 2016 Jul 25.
The macrolide rapamycin inhibits mTOR (mechanist target of rapamycin) function and has been broadly used to unveil the role of mTOR in immune responses. Inhibition of mTOR on dendritic cells (DC) can influence cellular immune response and the survival of DC. RSV is the most common cause of hospitalization in infants and is a high priority candidate to vaccine development. In this study we showed that rapamycin treatment on RSV-infected murine bone marrow-derived DC (BMDC) decreases the frequency of CD8(+)CD44(high) T cells. However, inhibition of mTOR on RSV-infected BMDC did not modify the activation phenotype of these cells. RSV-RNA levels increase when infected BMDC were treated with rapamycin. Moreover, we observed that rapamycin diminishes apoptosis cell death of RSV-infected BMDC co-culture with T cells and this effect was abolished when the cells were co-cultured in a transwell system that prevents cell-to-cell contact or migration. Taken together, these data indicate that rapamycin treatment present a toxic effect on RSV-infected BMDC increasing RSV-RNA levels, affecting partially CD8 T cell differentiation and also increasing BMDC survival in a mechanism dependent on T cell contact.
大环内酯类药物雷帕霉素可抑制雷帕霉素作用靶点（mTOR）的功能，已被广泛用于揭示mTOR在免疫反应中的作用。抑制mTOR对树突状细胞（DC）的作用可影响细胞免疫反应及DC的存活。呼吸道合胞病毒（RSV）是婴儿住院的最常见原因，也是疫苗研发的重点候选对象。在本研究中，我们发现用雷帕霉素处理受RSV感染的小鼠骨髓来源的DC（BMDC）会降低CD8(+)CD44(高) T细胞的频率。然而，抑制mTOR对受RSV感染的BMDC的激活表型并无影响。用雷帕霉素处理受感染的BMDC时，RSV-RNA水平会升高。此外，我们观察到雷帕霉素可减少与T细胞共培养的受RSV感染的BMDC的凋亡细胞死亡，而当细胞在防止细胞间接触或迁移的Transwell系统中共培养时，这种作用会消失。综上所述，这些数据表明，雷帕霉素处理对受RSV感染的BMDC具有毒性作用，会增加RSV-RNA水平，部分影响CD8 T细胞分化，并通过依赖T细胞接触的机制增加BMDC的存活。
