[Positive selection of a T cell repertoire during intrathymic differentiation]

Abstract

In SWR mice most of thymocytes bearing a high density V beta chain of T cell antigen receptor (TCR), V beta 17a brightly positive cells, were biased to CD4+8- subpopulation, whereas such thymocytes from SJL mice resided in both CD4+8- and CD4-8+ subpopulations. To elucidate the mechanism underlying the apparent difference in the thymocyte population, CD4/CD8 phenotype of thymocytes bearing high V beta 17a was analyzed in bone marrow (BM) chimeras in which SWR or SJL mice were used as BM donors and various strains of mice as recipients. When SWR precursor cells developed in SJL or B10 thymus, the proportion of V beta 17a+CD4-8+ thymocytes was expanded to the level of that seen in normal SJL mice. By contrast, the proportion of SJL derived V beta 17a+ CD4-8+ thymocytes which had developed in SWR or DBA/1 thymus was reduced to the level of that in normal SWR mice. An intermediate proportion was observed when SWR precursor cells had developed in the thymus of B10.A(4R). It was revealed that H-2K molecules expressed on thymic epithelial cells is one of the determinants which influence the proportion of V beta 17a+CD4-8+ thymocytes. In addition, a hierarchy of selective pressure among the different H-2K haplotypes was present, such as Ks,b greater than Ks/q,k greater than Kq. Fine analysis of the H-2K molecules in which several kinds of H-2Kb mutant (bm) mice were used as recipients to prepare bone marrow chimeras demonstrated that substitutions of amino acids at a region on the beta-pleated floor of antigen recognition site reduced significantly the proportion of V beta 17a+CD4-8+ cells. According to the three-dimensional class I structure, TCR are unable to access directly to this region. Thus, the present finding suggests that the substitutions of amino acids at this site alter the shape and charge of peptide binding site of H-2K molecules and eventually influence the positive selection of the V beta 17a+ T cell repertoire during differentiation.