Induction of neonatal tolerance to the Mls-1a self-super-antigen. Time kinetics and MHC restriction.

Abstract

We examined the accessibility of the thymus to a self-super-Ag encoded by the Mls-1a region of chromosome 1 and the process by which this Ag establishes immunologic tolerance. Intravenously administered Mls-1a Ag accumulates quickly in peripheral organs of adult or newborn Mls-1a- recipients, where it mounts an immune response. The Ag does not enter the thymus in detectable amounts and does not induce an immune response of Mls-1a-responsive T cells present in this organ. Instead, the thymus of newborn Mls-1a- recipients of Mls-1a+ lymphoid cells continues for several days to export Mls-1a-reactive T cells, which respond to Mls-1a Ag when they encounter it in peripheral organs. This response peaks around day 3 or day 4 and declines very rapidly thereafter. The deletion of intrathymic Mls-1a-reactive T cells ensues simultaneously with this decline. It has previously been shown that Mls-1a Ag causes deletion or anergy of Mls-1a-reactive peripheral T cells, subsequent to their activation. We see the same time kinetics in producing deletion or anergy of Mls-1a-reactive T cells in the thymus of newborn animals, with the exception that the activation phase that precedes the deletion of Mls-1a-reactive T cells occurs in the periphery and not in the thymus. This observation indicates that thymic Mls-1a-specific T cells are not deleted through activation. Whether their deletion depends on a feed-back from the peripheral activation of Mls-1a-reactive cells, as the time relationship could suggest, is not clear. The finding establishes, however, that the deletion of functionally mature Mls-1a-reactive T cells and the activation of such cells are not necessarily related events, which may or may not utilize a common trigger mechanism, such as the engagement of the TCR. Concerning the trigger mechanism, we report that Mls-1a-specific deletion of T cells is an MHC-restricted process, whereas Mls-1a-specific activation of T cells is not MHC restricted.