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Individual T cell receptor (TCR) V^sub alpha^ elements are expressed preferentially in CD4 or CD8 peripheral T cell subsets. The closely related V^sub alpha^.3.1 and V^sub alpha^3.2 elements show reciprocal selection into CD4 and CD8 subsets, respectively. Transgenic mice expressing sitedirected mutants of a V^sub alpha^3.1 gene were used to show that individual residues in either the complementarity-determining region 1 (CDR1) or CDR2 were sufficient to change selection from the CD4 subset to the CD8 subset. Thus, the germline-encoded V^sub alpha^ elements are a major influence on major histocompatibility class complex (MHC) restriction, most likely by a preferential interaction with one or the other class of MHC molecule.
Thymocytes that are positively selected on MHC class I proteins become peripheral CD8+ cells and those positively selected on MHC class II proteins become CD4+ peripheral T cells (1). An alpha(beta) TCR transgene from a CD8+ T cell causes most T cells bearing that receptor to be positively selected into the CD8+ compartment (2), whereas a transgenic TCR from a CD4+ cell shows similarly skewed expression in the CD4+ population (3). Less extreme skewing into the CD4 or CD8 peripheral T cell subset is also seen with individual V regions-most noticeably with V. regions, which are preferentially expressed in one or the other subset (4-9). This phenomenon is largely independent of MHC haplotype and suggests either that individual V^sub alpha^ regions react preferentially with class I or class II molecules or that particular V^sub alpha^ regions associate with the CD4 or CD8 coreceptors.
The structure of the TCR V^sub alpha^domain has recently been determined (10).^sup alpha^ The CDR3 segments of TCR V^sub alpha^ and V^sub beta^, [produced by VJ or V(D)J recombination, respectively] are predicted to lie centrally in the combining site of the TCR ( 10, 11 ). If CDR3 interacts with the peptide bound in the MHC groove, the less variable germline-encoded CDR1- and CDR2-equivalent regions would be available to interact with the MHC alpha helices. Thus, the skewed expression of V^sub alpha^, elements in CD4 and CD8 subsets suggests that the CDR1 and CDR2 of V^sub alpha^ could play a role in distinguishing between class I and II. Closely related members of the V^sub alpha^3 family undergo selection by different MHC classes (7,...