How Do Immune Cells Become Less Dogmatic than Human-being during Data Processing? The Effect of Flexible Epistemology on Immune Cells

Peter Riezebos Inverted Dogmatic Paradigm (1/3)

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 Major histocompatibility complex (MHC) is the gene cluster that has immensely polymorphic character. MHC gene cluster encodes MHC surface proteins which involve in antigen presentation directly. Antigen-presentation is serving a protein fragment to other relevant cells in order to create an immunological response. This protein fragment presentation is highly important for adaptive immunity and also it involves in triggering apoptosis of cells that secrete misfolded protein fragment. Basically, MHC molecules are glycoproteins that serve antigens to T cells. In human genome, MHC –gene clusters are located on chromosome 6 and encodes α/β subunit proteins of MHC molecules (Figure 1). 

Figure 1. Major Histocompatibility Complex (MHC)- Types and Structure

There are mainly three groups of MHC molecules which is numerated as MHC I, MHC II and MHC III¹.  In all nucleated cells, MHC I which, contains 3 α and β-microglobulin protein, is located on the cell surface and interacts with cytotoxic T cells, CTLs (CD+8). Antigens that degraded in cytosol bind to MHC I molecules without overhangs and resulted in apoptosis via CTLs. As distinct from MHC I, intravesicular and extracellular antigens’ peptides bind to MHC II molecules groove and it activates CD+4 T cells (Th) which stimulate other immunological cells or mechanisms. So, MHC II molecules are present only in professional antigen-presenting cells (APCs) such as dendritic cells, B cells and macrophages. Peptide binding on MHC II groove is different from MHC I in terms of being overhangs in both ends of peptide that binds to cleft². Hence, antigens that bonded to MHC II molecules are recognized by T Cell Receptors (TCRs) of CD+4 T cells. An additional interaction between B7 protein & CD28 receptor is also needed for proper activation (Figure 2). 

Figure 2. Structure of MHC-peptide-TCR complexes.

These sharp characteristic differences between MHC I & II molecules dictate fate of response (Figure 3) by virtue of either endogenous or exogenous degraded antigens³. Exogenous antigens mainly bind to MHC II molecules, though. Sometimes MHC I molecules can capture exogenous antigens which is described as unlawful (unexpected) usage of class I molecules. Such phenomena involving exogenous antigen-MHC I interaction are described as cross-presentation (Figure 4). Cross-presentation is mainly occurred by dendritic cells (DCs) via their endocytic/ phagocytic adaptions. During cross-presentation, two pathways are named cytosolic and vacuolar pathway may be chose depending on antigen processing⁴.

Figure 3. Antigen Presentation of MHC I & MHC II

Figure 4. Cross-presentation by dendritic cells.

References
  

1.      Rock, K. L., Reits, E., & Neefjes, J. (2016). Present Yourself! By MHC Class I and MHC Class II Molecules. Trends in immunology, 37(11), 724–737. https://doi.org/10.1016/j.it.2016.08.010

2.      Neefjes, J., Jongsma, M. L., Paul, P., & Bakke, O. (2011). Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nature reviews. Immunology, 11(12), 823–836. https://doi.org/10.1038/nri3084

3.      Wieczorek, M., Abualrous, E. T., Sticht, J., Álvaro-Benito, M., Stolzenberg, S., Noé, F., & Freund, C. (2017). Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Frontiers in immunology, 8, 292. https://doi.org/10.3389/fimmu.2017.00292

4.      Joffre, O. P., Segura, E., Savina, A., & Amigorena, S. (2012). Cross-presentation by dendritic cells. Nature reviews. Immunology, 12(8), 557–569. https://doi.org/10.1038/nri3254

MUSTAFA ÖZTÜRK, revised from Immunology Course Assignments