Antigen presentation plays a pivotal role in the immune system through which pathogenic antigens are processed and coupled along with major histocompatibility complex (MHC), and presented to T cells for their effector response. Macrophages, B cells and dendritic cells are the primary antigen presenting cells (APC’s). Intracellular antigens generated by viruses, or some cytoplasmic bacterial antigens are digested by the host cells and coupled with MHC Class I by Transporter associated with antigen Processing complex (TAP), which transports them to the cell surface and presents to CD8+ cytotoxic T cells (Germain, R 1994). These cells elicit a cytotoxic response on the infected target cells. Extracellular antigens or exogenous pathogens like bacteria, parasites are captured by phagocytosis and processed by dendritic cells in the lymph nodes and presented along with MHC II molecules to the CD4+ helper T cells, which function to facilitate the adaptive immune responses by release of various cytokines (Germain, R 1994). Antigen presentation is critical for generating tolerance by deletion of self-reactive T cells in the thymus. Cross-presentation is the process through which extracellular antigens from certain viruses and tumors that do not readily infect APCs, are processed and presented with MHC I molecules to CD8+ cytotoxic T cells and generate effective immune responses against these pathogens (Health, W and Carbone 2001).
Function of dendritic cells in antigen presentation.
Dendritic cells (DCs) possess cell surface proteins and transcription factors essential for priming and activating naïve T cells in presence of exogenous antigens, which other APC’s like B cells,
macrophages and monocytes lack (Banchereau 2000). Studies on the DCs in the last decade have revealed their importance in cross presentation of tumor antigens.
Cross-presentation of Antigens
The phenomenon of cross-presentation was first observed in 1976 by Michael J. Bevan, after the injection of cells containing alloantigenic MHC molecules into syngenic mice, which activated the CD8+ T cell responses induced by the APC’s of the recipient (Bevan 1976). Cross presentation allows for generation of an immune response against certain type of viruses, bacteria and tumors which usually evade an immune response by suppressing antigen presentation (Huang 1994).
Role of DC subsets in Tumor Antigen Cross-presentation.
DCs are important APC’s of the immune system, besides macrophages and B cells. Generally DCs are classified as CD11c+ cells which are further subcategorized into subsets based on the various transmembrane protein markers (Joffre 2012). The ability of these cells to cross-present is considered instrumental for cytotoxic immune responses against tumor cell antigens, as illustrated in an in vivo model of mice that were depleted in CD11c+ cells and showed ablated T cell responses (Jung 2002). A study has demonstrated that the CD8a+ DCs were indispensable for the formation of tumor specific cytotoxic T lymphocytes (CTLs), since lack of Batf3 gene in transgenic mice led to a selective deletion of CD8a+ DCs from the lymph node and spleen of these mice. Subcutaneous injection of fibrosarcomas into these mice led to growth of these tumors, which are otherwise rapidly rejected by tumor- specific CTLs (Hildner 2008). It is not very clearly understood if the reduced CTL responses in absence of CD8a+ DCs is due to lack of cross-presentation by the CD8a+ DCs or due to a decrease in the interleukins secreted by these subset, which have otherwise been shown to enhance cross presentation of these tumor antigens (Mashayeki 2011). Studies on DC cross- presentation have shown that the various DC subsets exhibit distinctive capabilities of antigen presentation to T cells. For example, CD8a+ DC cells are efficient in lymphoid tissues whereas migratory CD8 a- CD103 +/- are efficient in cross presenting the antigens in the tissues like lung and skin. Thus it could be concluded that the ability of a DC subset to cross present antigens depends on the nature of the antigen and location of the tissue. The human counterpart of CD8DCs are the BDCA-3 + DCs which have been shown to migrate into renal carcinoma (Gigante 2009) and found to have decreased substantially in hepatocarcinoma patients relative to healthy normal controls (Beckebaum 2004). However, their specific function in presentation of tumor antigens is unclear and needs further evaluation. An exciting finding that spurts a great interest in the role of DCs in tumor antigen presentation is the study that dying malignant tumor cells injected in mice as anti-cancer vaccine activate adaptive immunity responses (Buckwalter, M 2013). In vivo models in mice injected with either apoptotic or necrotic cells have shown contradictory results for their effects on CD8+ cytotoxic cell response. One study shows how apoptosis favors the CTL response tumors relative to necrosis (Scheffer, R 2003 & Gamrekelashwili, J 2012), whereas another study demonstrates no difference in the effect of the two cell death mechanisms on these responses (kotera, Y 2001). There is also evidence for another form of programmed cell death called autophagy being involved in phagocytosis and presentation of tumor antigens by DCs to CTLs (Uhl, M 2009). Although these observations clearly demonstrate that dying cells (apoptotic/necrotic/autophagic) facilitate antigen presentation and CTL immune responses, there is a lack of understanding of which specific subsets of DCs preferentially favor which form of cell death in this process. Also, experimental methods which have loaded DCs with apoptotic or necrotic cells in the form of DC vaccines fail to address and specify the details of how the cells are handled during injection and whether the debris or the lysate portion of the cells are administered.
Further studies would be required to answer the unresolved questions in order to better understand the use of DC vaccines for cancer.
Objectives: It would be interesting to study the specific interaction of molecules between the BDCA3+ DCs and the tumor antigens and understand their mechanism of presentation. It is also crucial to design experiments in vivo wherein the effect of individual subsets with specific transcriptional profiles can be evaluated for their preferential presentation of apoptotic/necrotic/autophagic antigens and compare the results.
Cross presentation is an ingenious mechanism evolved by the immune system to counteract the manipulation strategies and evasion of certain viruses and tumors, which have adapted the direct antigen presentation pathway. Of the known APCs, DCs are the most well studied cells which have been proven to be amenable for vaccine development against these viruses and tumors. Further experimentation and a deeper understanding of the specific subsets and extension in vivo models are crucial for vaccine development and treatment of these challenging pathogens.
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