Direct Presentation of MHC Alloantigens

In direct presentation, an intact MHC molecule is displayed by donor antigen-presenting cells (APCs) in the graft and recognized by recipient T cells without a need for host APCs. It may seem puzzling that T cells that are normally selected during their maturation to be self MHC restricted are capable of recognizing foreign (allogeneic or xenogeneic) MHC molecules. In fact, as we will discuss in more detail later, the frequency of T cells in a normal individual that recognize a single allogeneic MHC molecule is as high as 1% to 2% of all T cells, which is 100 to 1000 times greater than the frequency of T cells specific for any microbial peptide displayed by self MHC molecules. There are several likely explanations for this surprisingly strong recognition of foreign MHC molecules.

• The structure of all T cell receptors (TCRs) is inherently biased to recognize MHC molecules, even before selection in the thymus. In other words, TCR genes have evolved to encode a protein structure that has some, probably low, intrinsic affinity for MHC molecules. During T cell development in the thymus, positive selection results in survival of T cells with weak self MHC reactivity, and among these T cells, there may be many with strong reactivity to allogeneic MHC molecules. Also, negative selection in the thymus efficiently eliminates T cells with high affinity for self MHC (see Chapters 8 and 14), but it does not necessarily eliminate T cells that bind strongly to allogeneic MHC molecules, simply because these molecules are not present in the thymus. The result is that the mature repertoire has an intrinsic weak affinity for self MHC molecules and includes many T cells that bind allogeneic MHC molecules with high affinity.

• The structure of an allogeneic MHC molecule is similar enough to self MHC that many self MHC-restricted T cells recognize the foreign MHC molecule. In other words, an allogeneic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus a particular foreign peptide (Fig. 16-5). Direct allorecognition is an example of an immunologic cross-reaction in which a T cell that was selected to be self MHC restricted is able to recognize the structurally similar allogeneic MHC molecules. A single allogeneic MHC molecule may resemble many combinations of self MHC plus different bound pep-tides because of amino acid differences between the allogeneic and self MHC molecules. In this case, multiple T cells specific for the various self MHC-peptide complexes may cross-react with the single allogeneic MHC molecule.

• Many peptides may combine with a single MHC molecule and further expand the number of T cells that can recognize these combinations. MHC molecules that are expressed on cell surfaces normally contain bound peptides, and the peptides form part of the structure recognized by the alloreactive T cell, exactly like the role of peptides in the normal recognition of foreign antigens by self MHC-restricted T cells (Fig. 16-5C). Most of these peptides are likely to be self peptides that are the same in the donor and the recipient, but the donor peptides are displayed by allogeneic MHC molecules and therefore appear different from self peptide-self MHC complexes.

• All the MHC molecules on a donor APC will be foreign and will be recognized by alloreactive T cells; in contrast, in the case of an infection, less than 1% (and perhaps as few as 0.1%) of the MHC molecules on an APC normally present microbial peptides at any time and are recognized by T cells.

Direct allorecognition can generate both CD4+ and

CD8+ T cells that recognize graft antigens and contribute to rejection. This aspect of the alloreactive T cell response is described later.

Self MHC molecule presents foreign peptide to T cell selected to recognize self MHC weakly, but may recognize self MHC-foreign peptide complexes well

The self MHC-restricted T cell recognizes the allogeneic MHC molecule whose structure resembles a self MHC-foreign peptide complex

The self MHC-restricted T cell recognizes a structure formed by both the allogeneic MHC molecule and the bound peptide

FIGURE 16-5 Molecular basis of direct recognition of allogeneic MHC molecules. Direct recognition of allogeneic MHC molecules may be thought of as a cross-reaction in which a T cell specific for a self MHC molecule-foreign peptide complex (A) also recognizes an allogeneic MHC molecule (B, C). Nonpolymorphic donor peptides, labeled "self peptide," may not contribute to allorecognition (B) or they may (C).

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