The invariant chain, which associates with the major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, serves two functions important in antigen processing. First, it prevents class II molecules from binding peptides in the early stages of intracellular transport. Second, it contains a cytoplasmic signal that targets the class II-invariant chain complex to an acidic endosomal compartment. Proteolytic cleavage and subsequent dissociation of the invariant chain then occurs, allowing peptides derived from endocytosed proteins to bind to released class II molecules before their expression at the cell surface. Certain human cell lines that are mutant in one or more MHC-linked genes are defective in class II-restricted antigen processing. Here we show that in transfectants of one of these cell lines, T2, this deficiency results in the association of a large proportion of class II molecules with a nested set of invariant-chain-derived peptides (class II-associated invariant chain peptides, or CLIP). HLA-DR3 molecules isolated from T2 transfectants can be efficiently loaded with antigenic peptides by exposure to a low pH in vitro, perhaps reflecting the in vivo conditions in which peptides associate with class II molecules. Addition of synthetic CLIP inhibits the loading process, indicating that CLIP may define the region of the invariant chain responsible for obstructing the class II binding site.
The CD8 ؉ T cell diaspora has been analyzed after secondary challenge with an influenza A virus that replicates only in the respiratory tract. Numbers of D b NP366-and D b PA224-specific CD8 ؉ T cells were measured by tetramer staining at the end of the recall response, then followed sequentially in the lung, lymph nodes, spleen, blood, and other organs. The extent of clonal expansion did not reflect the sizes of the preexisting memory T cell pools. Although the high-frequency CD8 ؉ tetramer ؉ populations in the pneumonic lung and mediastinal lymph nodes fell rapidly from peak values, the ''whole mouse'' virus-specific CD8 ؉ T cell counts decreased only 2-fold over the 4 weeks after infection, then subsided at a fairly steady rate to reach a plateau at about 2 months. The largest numbers were found throughout in the spleen, then the bone marrow. The CD8 ؉ D b NP366 ؉ and CD8 ؉ D b PA224 ؉ sets remained significantly enlarged for at least 4 months, declining at equivalent rates while retaining the nucleoprotein > acid polymerase immunodominance hierarchy characteristic of the earlier antigendriven phase. Lowest levels of the CD69 ''activation marker'' were detected consistently on virus-specific CD8 ؉ T cells in the blood, then the spleen. Those in the bone marrow and liver were intermediate, and CD69 hi T cells were very prominent in the regional lymph nodes and the nasal-associated lymphoid tissue. Any population of ''resting'' CD8 ؉ memory T cells is thus phenotypically heterogeneous, widely dispersed, and subject to broad homeostatic and local environmental effects irrespective of epitope specificity or magnitude.T he vertebrate immune system is dynamic, mobile, and anatomically dispersed. Mammalian immune responses are thought to develop predominantly in the circumscribed microenvironments of the secondary lymphoid tissue, the lymph nodes (LNs), spleen, and foci embedded in mucosal sites such as the Peyer's patches (PP). However, the cellular elements of immunity, particularly the CD4 ϩ and CD8 ϩ T cells, are known to move via blood and lymph through a spectrum of other organs that are not normally considered to be part of the immune system. Measuring the extent of this lymphocyte diaspora has only recently become possible with the development of tetrameric complexes of MHC class I glycoprotein ϩ peptide (tetramers) for the direct, flow cytometric identification of antigen-specific CD8 ϩ T cells (1Ϫ5). The tetramers allow us to quantitate both the CD8 ϩ T cell response to pathogens and the subsequent return to homeostasis after the elimination of the invading organism.Analysis of the diaspora effect in viral immunity should optimally distinguish between the antigen-driven dispersion of CD8 ϩ effectors to sites of virus replication and distribution profiles ref lecting the normal physiology of lymphocyte recirculation. The latter will be more characteristic of a localized infection. The inf luenza A viruses replicate only in respiratory epithelium, although they also can undergo a defective growth cycle in ot...
The T-cell receptor (TCR) gamma polypeptide is expressed associated with CD3 (T3) on the surface of normal human peripheral blood lymphocytes. These cells function as non-MHC-restricted cytotoxic T lymphocytes (CTL)and thus may play an important role in host immune defence. The TCR gamma polypeptide occurs as a dimer in at least two molecular forms based on the absence or presence of disulphide linkage. These forms use TCR gamma polypeptides with strikingly different peptide backbone sizes.
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