SKINIMMUNITY · The Role of Langerhans Cells in T-Cell Priming During Intradermal Naked DNA Immunization
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2008-09-01 → 2012-08-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Кои видове дендритни клетки в кожата активират Т-клетките при ваксинация с плазмидна ДНК или лентивирусни вектори. Разбирането на този процес помага да се разбере как различните видове ваксини стимулират имунния отговор.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The Role of Langerhans Cells in T-Cell Priming During Intradermal Naked DNA Immunization
Plasmid DNA and lentiviral vectors are potent vaccine modalities that effectively induce cellular immune responses. Following intradermal immunisation, dendritic cells (DCs) migrate from the skin to the draining lymph nodes (LN) in order to present vector-encoded antigen to T cells for their specific activation. Skin DCs can be divided into at least three subsets: epidermal Langerhans cells (LCs), langerin-positive dermal DCs (Ln+ dDCs) and langerin-negative dermal DC (dDCs). The precise role of each DC subset in skin immunisation remains controversial and appears to depend on the nature of the infectious agent or vector employed. In this study we employed plasmid DNA and lentiviral vectors to dissect the role of skin DC following intradermal immunisation. We characterised the role of each skin DC subsets following immunisation with plasmid DNA (Elnekave-M et al. 2010 Journal of Immunology) and lentivectors (Furmanov-K et al. 2010 Journal of Immunology). We demonstrated that the noted vaccine modalities differentially activated skin DCs for induction of antigen-specific CD8+ T cells. While langerin-expressing DCs (i. e. LCs and/or Ln+ dDCs) were crucial for plasmid DNA-mediated immunity, these cells were negligible during immunisation with lentivectors as dDCs were the subset presenting antigen to T cells. We further analyzed DC function in the described experimental setting. First, we characterised the origin and function of newly recruited LCs during inflammatory response generated by plasmid DNA immunisation, and found a unique role for LCs and their epidermal precursors in immune induction. In another project, we provided a novel explanation for the inability of lentivectors to activate efficiently memory T cells following boosting intradermal immunisation. We demonstrated that lentivectors trigger exceptionally slow kinetics of antigen expression in the skin, while optimal activation of lentivector-induced T cells relays on durable expression of the antigen. These qualities hamper secondary responses, since lentivector-encoded antigen is rapidly cleared by primary cytotoxic T cells that limit its presentation by skin DCs. Finally, we extended our research to DCs of the oral mucosa. We used plasmid DNA to dissect the role of oral DCs in distinct niches of the oral cavity (the buccal versus the lining mucosa). Our results indicate that each oral mucosal tissue engaged different subsets of DCs for T-cell immune induction (Nudel-I et al. 2011 journal of Immunology). Taken together, the data generated by the above studies should increase our understating on the immunological mechanisms involve in genetic immunisation. We hope that this knowledge will be translated in future vaccine studies in order to modulate skin immunity and to improve vaccine efficacy.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a dominant role in initiating T-cell responses. The skin is populated by at least two subsets of DCs: Langerhans cells (LCs), which form a contiguous network throughout the epidermis, and dermal DC. According to the conventional paradigm, LCs perform a sentinel function by detecting skin pathogens and integrating this information to T cells in the lymph nodes (LNs). However, recent data have highlighted only the importance of dermal DC in skin immunity, while the role of LCs remains an enigma. The arrival of skin DCs to the LNs and activation of CD8+ T cells are thought to take place within 24 hrs after exposure to an antigen. We have recently described that following intradermal immunization with plasmid DNA, CD8+ T cell priming initiates 4 days post-immunization and reaches its maximal level on day 15. We also showed that arrival of APCs from the skin occurs 3 days after the immunization and proceeds for almost two weeks. Such pattern of migration is consistent with the reported migration kinetics of LCs but not of dermal DCs that enter the LN within the first 24 hrs post-immunization. We recently generated unpublished data demonstrating that T-cell priming correlates with the late arrival of CD11c+DEC205med cells (LCs) and not with that of CD11c+DEC205hi cells (dermal DCs) that are first to enter the LNs. This has led us to the hypothesis that LCs might play an important role in T-cell priming during intradermal DNA immunization. Using cellular immunology approaches and langerin-DTR and CD11c-DTR transgenic mice, we will address this issue by performing experiments falling under three specific aims. (i) Characterizing the type of skin DCs involve in antigen presentation. (ii) Identifying the factors leading to the slow-rate antigen presenting activity. (iii) Assessing the quality of the elicited immunity. These complementary aims should reveal a novel role for LCs in T-cell priming.
Оригинален текст от CORDIS (на английски).
Участници
- THE HEBREW UNIVERSITY OF JERUSALEM · JerusalemКоординаторИзраел
Връзки
Данни: CORDIS, © Европейски съюз