Page 23 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 1 The Human Immune Response 9

independent sets of V-region and C-region genes. A large majority heterozygous at each major locus. In contrast to TCRs and Igs,
of peripheral blood T cells express αβ TCRs, with a small fraction the genes of the MHC are codominantly expressed. Thus, at a
expressing γδ TCRs (usually ≤5% in peripheral blood). There is minimum, an APC can express six class I molecules and six class
a higher representation of γδ T cells in certain tissues, particularly II molecules (the products of the two alternative alleles of three
those lining mucous membranes, where they may be specialized class I and three class II loci). This number is, in fact, usually
for recognition of heavily glycosylated peptides or nonpeptide an underestimate, as a consequence of additional complexity in
antigens that are commonly encountered in these tissue compart- the organization of the class II region (Chapter 5).
ments. Thymocytes are committed to the expression of either
αβ or γδ TCR, and their differentiated progeny (T cells) never ANTIGEN PRESENTATION
change their TCR type in the periphery.
Because MHC genes do not undergo recombination, the number
Major Histocompatibility Complex of distinct antigen-binding grooves that they can form is many
MHC molecules constitute a third class of antigen-binding orders of magnitude less than that for either TCRs or Igs. Oli-
molecules. When an MHC class I molecule was initially crystal- gopeptides that bind to MHC molecules are the products of self
lized, an unknown peptide was found in a binding groove or foreign proteins. They are derived by hydrolytic cleavage within
formed by the first two (α 1 and α 2 ) domains of the molecule. APCs and are loaded into MHC molecules before expression at
This binding groove has since been established as a general the cell surface (Chapter 6). Indeed, stability of MHC molecules
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feature of MHC molecules. It is now known that the function at the cell surface requires the presence of a peptide in the
of MHC molecules is to present antigen to T cells in the form antigen-binding groove; cells mutant for the loading of peptide
of oligopeptides that reside within this antigen-binding groove fragments into MHC molecules fail to express MHC molecules
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(Chapter 6). The most important difference between the nature on their cell surfaces. Since in the absence of infection most
of the binding groove of MHC molecules and those of Ig and hydrolyzed proteins are of self-origin, the binding groove of
TCR is that the former does not represent a consequence of gene most MHC molecules contains a self-peptide. Class I and class
rearrangement. Rather, all the available MHC molecules in an II molecules differ from one another in the length of peptides
individual are encoded in a linked array, which in humans is that they bind, usually 8–9 amino acids for class I and 14–22
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located on chromosome 6 and designated the human leukocyte amino acids for class II. Although important exceptions are
antigen (HLA) complex. clearly demonstrable, they also generally differ with respect to
MHC molecules are of two basic types, class I and class II. the source of peptide. Those peptides binding to class I molecules
Class I molecules are found on the surface of almost all somatic usually derive from proteins synthesized intracellularly (e.g.,
cells, whereas cell surface expression of class II genes is restricted autologous proteins, tumor antigens, virus proteins, and proteins
primarily to cells specialized for APC function. Class I molecules from other intracellular microbes), whereas class II molecules
have a single heavy chain that is an integral membrane protein commonly bind peptides derived from proteins synthesized
comprised of three external domains (see Fig. 1.1). The heavy extracellularly (e.g., extracellular bacteria, nonreplicating vaccines,
chain is noncovalently associated with β 2 microglobulin, a toxins/allergens). Endogenous peptides are generated by the
nonpolymorphic, non–membrane-bound, single-domain Ig immunoproteasome and then are loaded into newly synthesized
superfamily molecule that is encoded in humans on chromosome class I molecules in the endoplasmic reticulum following active
15, not linked to the MHC. Class II MHC molecules, in contrast, transport from the cytosol. Proteolytic breakdown and loading
comprise two polypeptide chains, α and β (or A and B), of of exogenous peptides into class II molecules, in contrast, occurs
approximately equal size, each of which consists of two external in acidic endosomal vacuoles. As a consequence of proteolytic
domains connected to a transmembrane region and cytoplasmic processing and binding into an MHC molecule, T cells see linear
tail. Both chains of class II molecules are anchored on the cell peptide epitopes. In contrast, because B-cell antigen recognition
by a transmembrane domain, and both are encoded within the requires neither proteolytic processing nor binding into an MHC
MHC. Class I and class II molecules have a high degree of molecule, B cells recognize native, three-dimensional epitopes.
structural homology, and both fold to form a peptide-binding In addition to the recognition of lipids and lipid-conjugates
groove on their exterior face, with contribution from the α 1 and presented by CD1 molecules, there are other exceptions to the
α 2 domains for class I molecules and from α 1 and β 1 domains generalization that MHC molecules only present (and T cells
for class II. 25 only recognize) oligopeptides. It has been known for many years
There are three class I loci (HLA-A, -B, and -C) and three that T cells can recognize haptens, presumably covalently or
class II subregions (HLA-DR, -DQ, and -DP) that are principally noncovalently complexed with peptides residing in the antigen-
involved in antigen presentation to T cells (Chapter 5). The binding groove. This phenomenon is familiar to physicians as
functions of other class I and class II genes within this complex contact dermatitis to nonpeptide antigens, such as urushiol (from
are less clear. Some, at least, appear to be specialized for binding poison ivy) and nickel ion. Additionally, a newly recognized subset
(presentation) of peptide antigens of restricted type, source, or of T cells designated mucosal-associated (semi-)invariant T
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function (e.g., HLA-E), and others (e.g., HLA-DM and HLA-DO) (MAIT) cells recognize vitamin B 2 (riboflavin) and vitamin B 9
are clearly involved in antigen processing and loading of antigenic (folate) derivatives bound to MR1, a nonpolymorphic MHC
peptides into the binding cleft of the HLA-DR, -DQ, and -DP class I–like molecule; these vitamin derivatives are expressed by
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molecules (Chapter 6). Additionally, members of a family of many strains of bacteria and yeast. As MAIT cells constitute
“nonclassic” class Ib molecules, CD1 a-d , which are encoded on ~5% of human T cells and up to 25% of CD8 cells, their binding
chromosome 1, outside the MHC, are specialized for binding specificity suggests a role for these cells in host defenses. Addition-
and presentation of lipid and lipid-conjugate antigens to T cells. 14,28 ally, certain human γδ T cells can recognize a variety of nonpeptide
The HLA complex represents an exceedingly polymorphic phosphoantigens, such as phosphorylated nucleotides, other
set of genes (Chapter 5). Consequently, most individuals are phosphorylated small molecules, and alkylamines. The role of