MHC Restriction, Alloreactivity, and Thymic Education: A Common Link? Minireview (1989)

Philippe Kourilsky’ and Jean-Michel Claveriet * Biologic Molu Buus et al., 1987; Marrack and Kappler, 1988a; Sprent et al., 1988; Kourilsky and Claverie, 1989). We propose a new hypothesis on thymic education that could possibly provide a unifying view. MHC Restriction TH cells and CTLs most often show MHC-restricted rec- ognition of presented foreign antigen. That is, they act only when antigen is displayed by antigen-presenting cells that carry the same MHC molecules as the organism from which they were derived. Initially this was thought to imply direct recognition, by T cells (i.e., their TCR[sJ), of polymorphic MHC molecules. However, it was found, in line with the concept of determinant selection, that MHC molecules preferentially bind certain pieces of processed antigen and not others, and may also influence the struc- ture of the bound antigen. This is supported by a large body of data involving syn- thetic peptides and variant MHC molecules. First, certain peptides derived from the same antigen are active with certain MHC molecules and not others. This holds for class II and also for class I molecules. (For example, the T epitopes mapped thus far in influenza nucleoprotein are different in the haplotypes tested; Townsend, 1987.) Direct binding data are not yet available for ClaSS I molecules, but for class II binding of peptides largely correlates with their immunological properties (Al- len et al., 1987; Buus et al., 1987). Series of peptide ana- logs and variant MHC moiecules have been1 studied, situations have been found in which bindinlg takes place while recognition by T cell is altered. In such cases the most plausible interpretation is that MHC molecules in- fluence (select) the shape of the bound peptide. Thus, MHC molecules might be selective in two re- spects: in binding peptides and in shaping the bound pep- tides. The molecular basis of this selectivity only begins to be understood in the framework provided by HLA- A2 structure, and is the subject of active research. The extent of the selectivity is not known. It appears possible that the same peptide binds to a variety of MHC mole- cules. lmmunodominance of certain peptidios in a given antigen and skewing of T cell repertoires may also contrib- ute to MHC restriction (Gammon et al., 1987). Thus, MHC restriction would reflect the involvement of polymorphic residues in binding and/or shaping peptides, as well as in TCR recognition. Alloreactivity When cells displaying given MHC molecules are ex- posed, in vivo or in vitro, to other cells having a different MHC, a very strong immunological reaction1 follows. So- called alloreactive T cells are thus stimulated, as if their TCRs strongly reacted against the allo-MHC molecules. Another interpretation stems from the long tradition of immunological thinking concerning the recognition of self elements. The presentation of self components by MHC molecules has been postulated by a number of authors. The finding by Townsend et al. (1986) that the transfected gene encoding influenza nucleoprotein yields MHC class l-associated peptides on the cell surface has suggested that the transfected cell, not being itself an immune sys- tem, cannot “know” that the influenza gene is foreign; ac- cordingly, self proteins should be “presentable:’ and the cell surface might be coated by myriads of s’elf peptides. This hypothesis, known as the peptidic self model (Kouril- sky et al., 1987, and references therein), has numerous correlates regarding, in particular, the possible peptidic nature of certain minor transplantation antiglens and tu- mor antigens (De Plaen et al., 1988). Combined with the concept of determinant selection, it leads Uo definition of the immunologically relevant “self” as subset cellular peptides selected and presented in detectable amounts by self-MHC molecules, particularly class I. Thus, the latter would select self rather than be self. Accordingly, it was proposed that certain alloreactive reactions might be directed against the distinct set of pep- tides selected and presented by the distinct MHC mole- cules rather than against MHC molecules alone (Claverie and Kourilsky, 1986). The evidence that supports the presentation of self anti- gens (peptides) is growing. Lorenz and Allen (1988) have