Many fundamental features of T cell–mediated immunity are closely linked to the peptide display function of MHC molecules:

• The restriction of T cell recognition to MHC-associated peptides ensures that T cells see and respond only to cell-associated antigens. This is because MHC molecules are cell membrane proteins and because peptide loading and subsequent expression of MHC molecules depend on intracellular biosynthetic and assembly steps. In other words, MHC molecules can be loaded with peptides only inside cells, where intracellular and ingested antigens are present. Therefore, T lymphocytes can recognize the antigens of intracellular microbes, which require T cell–mediated effector mechanisms, as well as antigens ingested from the extracellular environment, such as those against which antibody responses are generated.

• By segregating the class I and class II pathways of anti gen processing, the immune system is able to respond to extracellular and intracellular microbes in different ways that are specialized to defend against these microbes (Fig. 1). Cytosolic antigens are processed and displayed by class I MHC molecules, which are expressed on all nucleated cells—as expected, because all nucleated cells can be infected with one or more species of viruses. Class I–associated peptides are recognized by CD8+ T lymphocytes, which differentiate into CTLs. The CTLs kill the infected cells and eradicate the infection, this being the most effective mechanism for eliminating cytoplasmic microbes. CTLs also kill tumor cells which produce cytosolic proteins from mutated genes. Many bacteria, fungi, and even extracellular viruses are typically captured and ingested by macrophages and their antigens are presented by class II molecules. Because of the specificity of CD4 for class II, class II–associated peptides are recognized by CD4+ T lymphocytes, which function as helper cells. These T cells help the macrophages to destroy ingested microbes, thereby activating an effector mechanism that can eliminate microbes that are internalized from the extracellular environment. B lymphocytes ingest protein antigens of microbes and also present processed peptides for recognition by CD4+ helper T cells. These helper cells stimulate the production of antibodies, which serve to eliminate extracellular microbes. Neither phagocytes nor antibodies are effective against intracellular viruses and other pathogens that can survive and replicate in the cytoplasm of host cells; cells harboring these cytosolic microbes are eliminated by CD8+ CTLs.

Thus, the nature of the protective immune response to different microbes is optimized by linking several features of antigen presentation and T cell recognition: the pathways of processing of vesicular and cytosolic antigens, the cellular expression of class I and class II MHC molecules, the specificity of CD8 and CD4 coreceptors for class I and class II molecules, and the functions of CD8+ cells as CTLs and of CD4+ cells as helper cells. The function of linking the type of microbe to one of the two antigen- processing pathways is important because the antigen receptors of T cells cannot distinguish between intra cellular and extracellular microbes. In fact, as previously mentioned, the same virus can be extracellular early after infection and becomes intracellular once the infection is established. During its extracellular life, the virus is fought by antibodies and phagocytes, whose production or functions are stimulated by helper T cells, but once the virus has found a haven in the cytoplasm of cells, it can be eradicated only by CTL-mediated killing of the infected cells. The segregation of class I and class II antigen presentation pathways ensures the correct, specialized immune response against microbes in different locations.

FIG1. Role of MHC-associated antigen presentation in recognition of microbial antigens by CD8+ and CD4+ effector T cells. A, Protein antigens of microbes that live in the cytoplasm of infected cells enter the class I MHC pathway of antigen processing. As a result, these proteins are recognized by CD8+ cytotoxic T lymphocytes, whose function is to kill infected cells. B, Protein antigens of microbes that are endocytosed from the extracellular environment by macrophages and B lymphocytes enter the class II MHC pathway of antigen processing. As a result, these proteins are recognized by CD4+ helper T lymphocytes, whose functions are to activate macrophages to destroy phagocytosed microbes and activate B cells to produce antibodies against extracellular microbes and toxins.

• The structural constraints on peptide binding to different MHC molecules, including length and anchor residues, account for the immunodominance of some peptides derived from complex protein antigens and for the inability of some individuals to respond to certain protein anti gens. When any protein is proteolytically degraded in APCs, many peptides may be generated, but only those peptides able to bind to the MHC molecules in that individual can be presented for recognition by T cells. These MHC-binding peptides are the immunodominant peptides of the antigen. Even microbes with complex protein antigens express a limited number of immunodominant peptides. Many attempts have been made to identify these peptides in order to develop vaccines, but it is difficult to select a small number of peptides from any microbe that would be immunogenic in a large number of people, because of the enormous poly morphism of MHC molecules in the population. The polymorphism of the MHC also means that some individuals may not express MHC molecules capable of binding any peptide derived from a particular antigen. These individuals would be nonresponders to that antigen. One of the earliest observations that established the physiologic importance of the MHC was the discovery that some inbred animals did not respond to simple protein antigens and responsive ness (or lack of) mapped to genes called immune response (Ir) genes, later shown to be class II MHC genes.

Finally, it should be mentioned that T cells also recognize and react against small molecules and even metal ions in an MHC-restricted manner. In fact, exposure to some small molecules that are used as therapeutic drugs and to metals such as nickel and beryllium often leads to pathologic T cell reactions (so-called hypersensitivity). There are several ways in which these nonpeptide anti gens may be recognized by MHC-restricted CD4+ and CD8+ T cells. Some of the chemicals are thought to covalently modify self-peptides or the MHC molecules themselves, creating altered molecules that are recognized as foreign. Other chemicals may bind noncovalently to MHC molecules and alter the structure of the peptide-binding cleft such that the MHC molecule can display peptides that are not normally presented and these peptide-MHC complexes are seen as being foreign.

مواضيع ذات صلة

C-type lectin receptors

Antigen Recognition by B cells and other Lymphocytes

العلاج المناعي المنفعل

الهروب من المراقبة المناعية

المناعة ضد الأورام

المستضدات المرتبطة بالأورام

علاقة التفاعلات المناعية بالأورام

Antigens Recognized by T Lymphocytes

Role of Innate Immunity in Stimulating Adaptive Immune Responses

الملامح المناعية للتحمل

الاضطرابات المناعية المرافقة لمرض AIDS

الخلل في نظام الخلايا البلعمية