MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation

RN Germain - Cell, 1994 - Elsevier
RN Germain
Cell, 1994Elsevier
The immune system has developed a variety of mecharmisms for sensing the presence of
invading microorganisms, which must be accomplished in the face of special topological
problems. Upon invasion of a multicellular hlost, a pathogen may reside either in the
extracellular space or within a cell's interior. Cell-associated receptors can readily detect
extracellular material but cannot directly recognize ligand separated from the receptor by a
lipid bilayer. The detection task is further complicated by the existence of two distinct …
The immune system has developed a variety of mecharmisms for sensing the presence of invading microorganisms, which must be accomplished in the face of special topological problems. Upon invasion of a multicellular hlost, a pathogen may reside either in the extracellular space or within a cell’s interior. Cell-associated receptors can readily detect extracellular material but cannot directly recognize ligand separated from the receptor by a lipid bilayer. The detection task is further complicated by the existence of two distinct subcompartmentsfor intracellular pathogen residence within a cell: the cytoplasm and membrane-bound endocytic organelles. Two types of immune recognition systems have evolved f’or dealing with organisms or pathogen-derived material outside of cells. One focuses on general characteristics of microorganisms, such as repeating polysaccharides in cell walls. The second is based on the specific recognition properties of immunoglobulin molecules, which constitute both the receptors and effector molecules of B lymphocytes. lmmunoglobulins can interact with a broad range of chemical structures, but their ligands must generally be on the outside of the invader, secreted by this organism, or expressed intact on the surface of infected host cells. If only these detection systems existed, pathogens could evade recognition by residing within cells of the host. The immune system therefore needed to develop a way of providing cell-bound receptors with an extracellular indication of intracellular invasion. To take advantage of lymphocyte-based adaptive immunity, this signal had to be specific for the infectious organism or its products. The solution that evolved is based on a simple fact: all pathogens differ from their hosts by at least one protein that can be uniquely represented as a short peptide sequence distinct from all host sequences of similar length. Provided that such peptides can be produced, captured, and stably expressed on the cell surface in adequate quantities, membrane-bound immune receptors can identify them, providing a general system for detection of intracellular pathogens.
The major histocompatibility complex (MHC) is agenetic region many of whose products are devoted to providing this extracellular representation of intracellular invasion. The MHCencoded class I and class II molecules serve as peptide-binding transport and display proteins, evoking effector responses upon recognition by the antigenspecific receptors of T lymphocytes. The two different classes of MHC molecules have evolved to deal with protein antigen localization in the cytosol versus membranebounded organelles. Other gene products, some also encoded within the MHC, participate in either the formation or translocation of peptides, or the trafficking of MHC molecules. Together, these events are referred to as antigen processing and presentation. The study of this area has begun to merge with investigations in nonimmunological systems of protein folding and chaperone function, intracellular protein targeting, transport, and degradation, and trafficking among intracellular organelles (Brodsky and Guagliardi, 1991; Germain and Margulies, 1993). This review will try to integrate specific immunological considerations with the general protein structural and cell biological themes that tie together accumulating information about MHC molecules and their peptide ligands.
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