THYMIC SKEWING OF THE CD4 CD8 RATIO MAPS WITH THE T-CELL RECEPTOR ALPHA-CHAIN LOCUS/

The thymic preference for CD4(+) T cells over CD8(+) T cells is often attributed to a default pathway favouring CD4(+) T cells [1] or to hom eostatic mechanisms [2,3] It is also clear, however, that T-cell recep tor (TCR) preferences for major histocompatibility complex (MHC) class I versus class II binding will strongly influence an individual clone 's skewing to the CD4 or CD8 subset [4] The variable region of each TC R alpha chain (V alpha) studied to date is found to be overrepresented in either CD4(+) [5-7] or CD8(+) cells [7-9], suggesting that each V alpha element can Interact more favourably with either MHC class I or class II molecules [10], Indeed, TCRs appear to have an intrinsic abil ity to interact with MHC molecules [11,12], and single amino acid resi dues present in germline-encoded complementarity determining region 1 (CDR1) and CDR2 of the V alpha element can be responsible for determin ing MHC specificity [13]. Interestingly, the degree of CD4/CD8 skewing is variable among different mouse strains [14,15] and in human popula tions [16], Here, we have shown that polymorphism in CD4/CD8 skewing b etween Be and BALB/c mice is determined by the stem cell genotype and not by environmental effects, and that it maps in or near the TCR alph a-chain complex, Tcra, This was confirmed by comparing Tcra(b) with Tc ra(a) or Tcra(c) haplotypes in congenic mice. We propose that the arra y of V alpha genes in various Tcra haplotypes exerts influence over th e proportion of CD4 and CD8 subsets generated and may account in part for the observed thymic skewing. Thus, while it has been suggested tha t the TCR genes have been selected by evolution for MHC binding, our r esults further indicate selection for class II MHC preference.