T-CELL DEVELOPMENT IN TCR-ALPHA-BETA TRANSGENIC MICE - ANALYSIS USINGV(D)J RECOMBINATION SUBSTRATES

The major pathway of intrathymic T cell differentiation leads CD4(-)8( -) (DN) T lineage-committed precursors to TCR-alpha beta(+) CD4(+)8(-) or CD4(-)8(+) (SP) T lymphocytes. The expression of functionally rear ranged TCR-alpha beta transgenes (Tg-TCR) may influence thymocyte deve lopment by affecting the various selection events that control T cell differentiation. To gain insights into these processes, we have produc ed double transgenic animals carrying V(D)J recombination substrates i n addition to the MHC class I (H-2K(b)) allospecific KB5C20 Tg-TCR. We have analyzed substrate rearrangements in purified populations of Tg- TCR(+) thymocytes in the situation of positive or negative selection. The profile of rearrangements found in SP thymocytes, positively selec ted for the Tg-TCR, suggests that expression of the KB5C20 Tg-TCR has only a minimal influence on substrate V(D)J recombination in cells dif ferentiating along the major crp T cell developmental pathway. In cont rast, Tg-TCR(+) DN thymocytes, in both positively and negatively selec ting haplotypes, presented a profile that implies premature cessation of substrate rearrangements. This profile was maintained in peripheral Tg-TCR(+) DN cells and was distinct from the one found in CD25(+), al pha beta(+), or gamma delta(+) DN cells purified from mice transgenic for the recombination substrates only. These results are discussed wit h respect to the possible origin and differentiation pathway of Tg-TCR (+) DN and SP cells.