genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
Extracellular antigens are presented by MHC-II molecules. After phagocytosis, these antigens
are degraded in the phagolysosome. Transport vesicles from the Golgi, which carry unloaded
MHC-II complexes, fuse to the phagolysosome, peptides are loaded to the MHC-II, and the
complete complex is transferred to the cell surface.
MHC-I serves the presentation of intracellular antigens. Here, the cleavage of proteins is
performed in the cytosol by the proteasome, a high molecular weight protease complex. Peptide
transporters transfer the peptides to the ER, where the loading of MHC-I molecules takes place.
Antigen presentation via MHC-II is restricted to professional antigen presenting cells (APC) of
the immune system, whereas presentation of intracellular antigens via MHC-I is additionally
present in many non-immune cells. Interestingly, natural killer (NK) cells, which belong to the
innate immune response and do not possess antigen specific receptors, sense the missing of
MHC-I presentation, which occurs in some virus-infected or cancer cells, and combat these cells
by inducing apoptosis (Jensen 1999).
The TCR of T cells is only able to bind MHC-peptide complexes tightly when the TCR features
the corresponding specificity to the peptide antigen. A very efficient system uses combination of
different TCR chains and somatic recombination, which is the removal of certain genomic
sections and recombining of the remaining parts, to generate an immense repertoire of different
T cell clones with different antigen specificity. These cells are additionally selected for nonreactivity
to the host’s own antigens and build a reservoir of defense cells for pathogenic
antigens which might interfere with the host during life-time. This is the distinctive feature of the
adaptive immune system: It carries the potential for the defense against almost every pathogen,
but it realizes in an adaptive manner with high specificity only the defense needed in the really
occurring case of infection, which makes it a time-consuming, but highly effective defense
mechanism against pathogens.
T-cells are subdivided into populations differing by the expression of surface antigens and by
the secreted cytokines, which in summary links them to distinct functions. The main two groups
are characterized by expression of CD4 or CD8. CD8 + T cells are cytotoxic effector cells. Their TCR
binds MHC-I molecules and therefore is able to recognize pathogenic intracellular antigens.
Specific binding in case of intracellular infection activates processes to destroy the cell and kill the
pathogen. CD4 + T cells are also called helper T cells. Their TCR binds to MHC-II molecules and thus
recognizes antigens derived after phagocytosis. In consequence, CD4 + T cells initiate mechanisms
fighting extracellular infection or disposing extracellular antigens. This is on the one hand a link
back to the innate immune cells, e. g. macrophages, which can be activated, but on the other a
link to a further aspect of the adaptive immune response. Besides the cellular adaptive immune
response the host commands an adaptive humoral immunity mediated by antibodies, which
originate from B cells (plasma B cells). In a process similar to the generation of specific TCR in
T cells, the B cell produces its own B cell receptor (BCR), which already includes the specificity of
the later antibodies. B cells are able to bind antigens via their BCR, phagocytose and degrade
them and finally present them on their surface as MHC-II-peptide complexes. An activated CD4 +
T cell with a specificity to this peptide can activate the B cell, which in turn starts further
differentiation steps and the production of antibodies. These antibodies autonomously bind their
specific antigen, and constitute an opsonization factor for the clearance of antibody-antigen
complexes by phagocytosis. Furthermore, they are the activation complex for the complement
system as described before (Janeway et al. 2002).
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