How mRNA vaccines Transfect cells and Express antigens?

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How mHow mRNA vaccines Transfect cells and Express antigens?

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How mRNA vaccines Transfect cells and Express antigens?

Brief description: The process of how mRNA vaccines transfect cells, express antigens, and activate immune cells.

mRNA transfected cells

Three types of cells transfected by mRNA vaccine in vivo

1. Transfection of somatic cells, such as muscle cells and epidermal cells
2. Transfection of resident immune cells at the injection site
3. Transfection of immune cells from secondary lymphoid tissues (lymph nodes and spleen)

Transfection and injection of local non-immune cells

Intradermal injection, intramuscular injection and subcutaneous injection of the mRNA vaccine can transfect non-immune cells near the injection site. Non-immune cells produce antigens, which are subsequently degraded in the proteasome. The degraded epitope forms a complex with MHC-I molecules, presents the antigen to CD8+ cytotoxic T cells, and activates immunity. The transfection of muscle cells can also activate dendritic cells and then cause CD8+ T cell initialization. Although the exact mechanism is unclear, it is believed that the antigen is transferred from muscle cells to dendritic cells.

Transfection of immune cells

mRNA vaccines can also transfect immune cells residing in tissues, mainly APCs (such as dendritic cells and macrophages). In vitro injection of mRNA vaccine can trigger a local immune response at the injection site, recruit immune cells to the area, and promote the resident immune cells in the transfected tissue. As in the first case, transfection of mRNA into these cells will result in antigen presentation on MHC I cells, leading to the activation of CD8+ T cells.

APCs can process antigens through the MHC class II pathway, leading to the activation of CD4+T helper cells.

However, priming CD4+ T cells is also essential for building strong cellular immunity. In addition, considering the role of T helper cells in B cell activation, the ability of mRNA vaccines to activate CD4+ T cells contributes to humoral immunity.

Transfection of immune cells from secondary lymphoid organs

The mRNA vaccine can also be drained by the lymphatic system and transported to neighboring lymph nodes through the lymphatic system. Lymph nodes are where various immune cells, including monocytes and naive T and B cells, live, and antigens located in these secondary lymphoid organs initiate an adaptive immune response. In the lymph nodes, the mRNA vaccine transfects resident cells, such as APCs and endothelial cells. Transfection of these cells can not only initiate T cells, but also B cell responses.

The mechanism of mRNA vaccine inducing adaptive immune response

1. Endocytosis-mediated internalization, the escape of mRNA from the endosome into the cytoplasm (see below for possible mechanisms), and the translation of ribosomes to produce antigenic proteins.
2. The antigen protein is degraded into fragments in the proteasome, and then presented by MHC-I.
3. Antigen protein can undergo lysosomal degradation through various mechanisms such as autophagy and signal peptide, and then be presented by MHC-II.
4. The antigen protein can be expressed outside the cell in a secreted or membrane-anchored form.
5. The antigen expressed outside the cell can be absorbed by APCs again and degraded by the lysosome.
6. In contrast, extracellular antigens can be recognized by B cell receptors on B cells, leading to B cell maturation.
7. MHC-I presents CD8+ T cell epitopes
8. MHC-II presents CD4+ T cell epitopes

Hypothetical mechanism of endocytic escape in nanocarriers

1. Nanocarriers can induce the instability of the endosome membrane to release genetic material from the cytoplasm
2. Nanocarriers, especially multimers, can scavenge protons and become cations in the acidic cavity of the nucleus cavity, causing more protons and counterions to flow in. This osmotic gradient induces water to flow into the endosome, causing the endosome to rupture.
3. The nanocarrier swells in acidic pH due to electrostatic repulsion and causes the endosome to physically break.

References:

Jeonghwan Kim et al, Self-assembled mRNA vaccines, Advanced Drug Delivery Reviews 170 (2021) 83–112

G. Lindgren, S. Ols, F. Liang, EA Thompson, A. Lin, F. Hellgren, K. Bahl, S. John, O. Yuzhakov, KJ Hassett, LA Brito, H. Salter, G. Ciaramella, K . Loré, Induction of robust B cell responses after influenza mRNA vaccination is accompanied by circulating hemagglutinin-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells, Front. Immunol. 8 (2017) 1539

N. Pardi, MJ Hogan, MS Naradikian, K. Parkhouse, DW Cain, L. Jones, MA Moody, HP Verkerke, A. Myles, E. Willis, CC LaBranche, DC Montefiori, JL Lobby, KO Saunders, H.- X. Liao, BT Korber, LL Sutherland, RM Scearce, PT Hraber, I. Tombácz, H. Muramatsu, H. Ni, DA Balikov, C. Li, BL Mui, YK Tam, F. Krammer, K. Karikó, P Polacino, LC Eisenlohr, TD Madden, MJ Hope, MG Lewis, KK Lee, L. Hu, SE Hensley, MP Cancro, BF Haynes, D. Weissman, Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses, J. Exp. Med. 215 (2018) 1571–158

N.L. Trevaskis, L.M. Kaminskas, C.J.H. Porter, From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity, Nat. Rev. Drug Discov. 14 (2015) 781–803

(source:internet, reference only)

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