CELLULAR IMMUNITY OF THE HUMAN FETUS AND NEONATE

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T lymphocytes (T cells) have surface antigen-specific T cell receptors (TCRs) composed of either an alpha (α) and a beta (β) chain (Fig. 1), or a gamma (γ) and a delta (δ) chain.31, 39 Both α/β- and γ/δ-TCRs are always associated with CD3, a complex of four proteins that signal to the interior of the T cell after engagement of the TCR by antigen (Fig. 1).103 The amino-terminal portion of each of the TCR chains is involved in antigen recognition and has a variable amino acid sequence. This variability is generated by rearrangement of TCR genes during T-cell development. The carboxy-terminal region is monomorphic or constant (C). The α/β-TCR recognizes protein antigens in the form of relatively short peptide fragments noncovalently bound to the groove of major histocompatibility complex (MHC) class I or class II molecules on the antigen-presenting cell (APC) (Fig. 1).90, 127 T cells bearing TCRs composed of α and β subunits (α/β-T cells, for short) predominate in the thymus, circulation, lymph nodes and spleen. T cells bearing TCRs made of γ and δ chains (γ/δ-T cells) have a tissue distribution and antigen specificity that are distinct from those of α/β-T cells and are discussed separately.

Class I MHC present peptides mainly to CD8 α/β-T cells. Virtually all cells of the body express class I MHC and contain the intracellular machinery required for generating peptides that bind to them. The histocompatibility leukocyte antigen (HLA)-A, B, and C heavy chains form the peptide-binding groove for human class I MHC and are associated with β2-microglobulin, a monomorphic light chain. Peptides bound to class I MHC molecules are typically only eight to nine amino acid residues in length and are mainly derived from proteins synthesized within the APC (Fig. 2). These peptides are usually fragments from normal self-proteins unless the cell's cytoplasm contains foreign protein (e.g., as a result of infection with an intracellular pathogen, such as a virus).

Class II MHC is mainly found on cells specialized for antigen presentation (e.g., dendritic cells, mononuclear phagocytes [Mφ], B cells, and thymic epithelial cells), and present peptides mainly to CD4 α/β-T cells.127 There are three types of class II MHC human molecules, DR, DP, and DQ, each consisting of an α and a β chain that together form a peptide-binding groove (see Fig. 1). The peptides binding to these molecules typically range in size between 14 and 16 amino acids. Most class II MHC peptides are derived from phagocytosis or endocytosis of soluble or membrane-bound proteins (see Fig. 2).127 The invariant chain protein prevents occupation of the groove until the class II MHC molecule reaches a specialized endocytic compartment, in which peptide loading takes place. Release of the invariant chain and the loading with peptide is facilitated by the HLA-DM molecule (see Fig. 2). Class II MHC-associated peptides are self-peptides unless the cell internalizes foreign proteins derived from infection, transplantation, or immunization.

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Address reprint requests to David B. Lewis, MD, Division of Immunology and Transplantation Biology, Stanford University School of Medicine, 300 Pasteur Drive, Room H-307, Stanford, CA 94305–5208, e-mail: [email protected]

This work was supported by Grants R01 HD97002 and R01 AI26940 from the National Institutes of Health.

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Division of Immunology and Transplantation Biology, Stanford University School of Medicine, Stanford, California