INFLUENCE OF RETINOIC ACID ON THE DIFFERENTIATION PATHWAY OF T-CELLS IN THE THYMUS

This study investigated the ability of retinoic acid (RA) to influence T cell differentiation. All-trans-RA had marked effects on T cell dif ferentiation in murine fetal thymic organ cultures (FTOCs). The time c ourse of the effect of all-trans-RA in FTOC of day 14 C57BL/6 embryos revealed a twofold increase in the frequency of CD4 single-positive (S P) cells and a high level of CD3-bearing cells (CD3(high) cells) at a later stage of T cell development. At an earlier stage, all-trans-RA i nduced a twofold increase in the frequency of CD4 SP cells, but signif icantly suppressed the upregulation of CD3 and TCR. Reverse transcript ion-PCR using RA receptor (RAR) subtype-specific primers showed that R AR alpha but not beta and gamma is expressed during T cell development in the thymus and that its expression was associated with the generat ion of CD4/CD8 double-positive (DP) cells. In FTOC of day 16 BALB/c em bryos, the level of V beta 3(high) cells was greatly reduced (1.4% of the CD3(high) cells) in response to the mouse mammary tumor virus-6-en coded superantigen, but V beta 3-bearing cells were rescued from the d eletion in the presence of all-trans-RA (5.6% of the CD3(high) cells). Further, the inhibitory effect of all-trans-RA on thymocyte deletion was observed when the deletion was induced by a low concentration of s taphylococcal enterotoxin B in FTOC. Taken together, these data sugges t that RA increases the frequency of mature and self-reactive T cells in the thymus, possibly by inhibiting the process of negative selectio n at the DP stage of T cell differentiation. (C) 1997 Academic Press.