Executive Summary
self-peptide/MHC complexes 作者:WL Lo·2013·被引用次数:24—The processing and presentation ofself-proteins is essential to develop an effective immune system, with almost all T cells only ever encountering
The self-peptide-MHC complex is a fundamental component of the immune system, playing a critical role in distinguishing between the body's own tissues and foreign invaders. This intricate molecular interaction involves major histocompatibility complex (MHC) molecules, which are cell surface proteins responsible for presenting peptide fragments to T cells. While the presentation of foreign peptides is essential for mounting an immune response against pathogens, the recognition of self-peptides by T cell receptors (TCRs) can, in certain circumstances, lead to detrimental outcomes such as autoimmune disease. Understanding the dynamics of self-peptide-MHC complexes is therefore paramount for comprehending immune health and disease pathogenesis.
MHC molecules, also known as human leukocyte antigens (HLAs) in humans, are highly polymorphic, meaning they exist in many different forms within a population. This diversity ensures that a wide range of peptides can be presented, enhancing the collective ability of a species to defend against diverse pathogens. There are two main classes of MHC molecules: MHC class I and MHC class II.
MHC class I molecules are found on the surface of almost all nucleated cells in the body. Their primary function is to display peptides derived from proteins synthesized within the cell's cytoplasm. This includes not only viral proteins but also self-proteins. Through a process called antigen processing, cellular proteins are broken down into small peptide fragments. These fragments are then transported into the endoplasmic reticulum, where they bind to newly synthesized MHC class I molecules. The resulting self-peptide-MHC complexes are subsequently transported to the cell surface. This constant presentation of self-peptides by MHC class I molecules is crucial for educating T cells during their development in the thymus. T cells that react too strongly to these self-MHC complexes are typically eliminated, a process known as central tolerance, thereby preventing self-reactive CD4+ Tconv cell populations from circulating freely.
In contrast, MHC class II molecules are primarily expressed on specialized antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. These cells are responsible for engulfing and processing extracellular material, including bacteria and other foreign pathogens. Proteins from these engulfed entities are broken down into peptides within specialized compartments (endosomes and lysosomes). These peptides are then loaded onto MHC class II molecules and presented on the APC surface. This presentation of foreign peptide fragments by MHC class II molecules is critical for activating helper T cells (CD4+ T cells), which orchestrate a broader immune response.
The interaction between the T cell receptor (TCR) and the peptide-MHC complex is highly specific. The TCR recognizes a particular combination of a peptide and the MHC molecule presenting it. While the immune system is exquisitely tuned to recognize foreign invaders, the presentation of self-peptides is not always benign. In certain situations, the immune system can mistakenly identify self-peptide-MHC complexes as foreign, triggering an autoimmune response. This can occur due to genetic predispositions, environmental factors, or a breakdown in the mechanisms that maintain self-tolerance. For instance, studies have shown that recognition of self-peptide-MHC complexes by autoimmune T cells can lead to tissue damage and chronic inflammation. The precise mechanisms by which self-peptide-MHC complexes are recognized or not recognized by T cells raised multiple questions in immunology for decades.
Research into self-peptide-MHC interactions has revealed complex nuances. For example, the major histocompatibility complex peptide complex can be viewed as a scaffold where the peptide is housed within the MHC molecule's binding groove. The structure of this groove, dictated by the specific MHC allele, influences which peptides can bind. Some studies have highlighted the unconventional topology of self peptide–major histocompatibility complex interactions, suggesting that TCR engagement with self-peptide/MHC complexes can occur with different topologies, some of which may be suboptimal for T cell activation, while others might contribute to disease.
The development of an effective immune system relies heavily on the proper processing and presentation of self-proteins. This ensures that T cells are adequately trained to distinguish between self and non-self. However, the line between tolerance and autoimmunity can be thin. The study of immunogenic self-peptides is a critical area of research aimed at understanding how certain self-peptides can escape immune surveillance and provoke an attack on the body's own tissues. The origin and role of MHC class I-associated self-peptides, for instance, are crucial for the development of certain T cell populations, underscoring the essential, yet sometimes precarious, role of self-MHC.
Furthermore, the concept of self versus foreign peptide-MHC complexes highlights the challenge faced by T cells. They must be able to recognize foreign antigens presented by MHC molecules while remaining tolerant to the body's own components. When
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作者:M Hahn·2005·被引用次数:304—T cell receptors (TCRs) recognizepeptidefragments bound tomajor histocompatibility complex(MHC) glycoproteins, and rearrangement of TCR gene
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