But positive selection is not the only basis for alloreactivity. This conclusion was implied by observations that T cells artificially driven to mature in animals lacking MHC class I and class II, in which positive selection in the thymus cannot occur, still display frequent alloreactivity. It appears that T-cell receptor genes encode the inherent ability to recognize MHC molecules. X-ray crystallographic studies of T-cell receptors bound to MHC molecules provide a structural basis for an inherent binding interaction (Fig. 6.24). Specific amino acid residues within the germline-encoded region of certain TCRβ genes interact with conserved features of the MHC molecule, implying a type of germlineencoded affinity. Given the large number of variable-region sequences in T-cell receptors, each T-cell receptor may bind MHC molecules in its own idiosyncratic way using both germline-encoded regions and variable regions.
In principle, alloreactive T cells might depend on recognizing either a foreign peptide antigen or the nonself MHC molecule to which it is bound for their reactivity against nonself MHC; these options have been called peptide-dependent and peptide-independent allorecognition. But as the number of individual alloreactive T-cell clones studied has increased, it seems that most alloreactive T cells actually recognize both; that is, most individual alloreactive T-cell clones respond to a foreign MHC molecule only when a particular peptide is bound to it. In this sense, the structural basis of allorecognition may be quite similar to normal MHC-restricted peptide recognition and be dependent on contacts with both peptide and MHC molecule (see Fig. 6.23, left panel), but in this case a foreign MHC molecule. In practice, alloreactive responses against a transplanted organ are likely to represent the combined
Fig. 6.24 Germline-encoded residues in CDR1 and CDR2 of V-region genes confer on T-cell receptors an inherent affinity for MHC molecules. Shown is the structure for several T-cell receptors bound to a class II MHC molecule. Conserved residues (Lys39, Gln57, and Gln61) within the α1 helix of the MHC (green) make an extended hydrogen-bonded network with germline-encoded and nonpolymorphic residues located in the CDR1 (Asn31) and CDR2 (Glu56, Tyr50) regions of the Vβ 8.2 gene, respectively. The configuration of these contacts is very similar between different structures, implying that the germline sequence of the CDR1 and CDR2 confers an inherent bias for T-cell receptor affinity for MHC. Courtesy of K.C. Garcia.
activity of many alloreactive T cells, and it is not possible to determine what peptides from the donor might be involved in recognition by the alloreactive T cells. We will return to alloreactivity when we discuss organ transplantation in more detail in Chapter 15.
6-14 Many T cells respond to superantigens.
Superantigens are a distinct class of antigens that stimulate a primary T-cell response similar in magnitude to a response to allogeneic MHC molecules. Such responses were first observed in mixed lymphocyte reactions using lymphocytes from strains of mice that were MHC-identical but otherwise genetically distinct. The antigens provoking this reaction were originally designated as minor lymphocyte stimulating (Mls) antigens, and it seemed reasonable to suppose that they might be functionally similar to the MHC molecules themselves. We now know that this is not true. The Mls antigens in these mouse strains are encoded by retroviruses, such as the mouse mammary tumor virus, that have become stably integrated at various sites in the mouse chromosomes. Superantigens are produced by many different pathogens, including bacteria, mycoplasmas, and viruses, and the responses they provoke are helpful to the pathogen rather than the host.