Cytotoxic T-cell precursors revealed in neonatally tolerant mice.

Abstract

Induction of neonatal tolerance leads to a profound reduction in cytotoxic T-lymphocyte precursor frequencies against the tolerated alloantigen ("tolerogen") as evaluated by limiting-dilution analysis. The curves obtained were linear within the range tested and, thus, did not yield evidence for any dissociation of cytotoxic precursors from regulatory cell populations. However, it could be shown that cytotoxic T-lymphocyte precursor frequencies against the tolerogen increased drastically if the tolerant spleen cells were adsorbed, prior to limiting-dilution culture, on monolayers of syngeneic blasts expressing receptors for the tolerogen but not if they were adsorbed on syngeneic blasts against third-party antigens. This finding implies that cytotoxic precursor cells against the tolerogen are not clonally deleted in tolerant animals but rather are suppressed by a regulatory cell population that is present at high frequency and presumably acts in an anti-idiotypic fashion.

Alloantigen persistence in induction and maintenance of transplantation tolerance.

“…This interpretation is entirely compatible with results presented by Stockinger (28) and Heeg et al . (29), who demonstrated removal of suppressor cells by adsorbance of tolerant cells on monolayers of syngeneic blasts bearing receptors for the given tolerogen.…”

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

“…The results described here will be discussed in the context of pretransplant transfusion effects (20)(21)(22)(23)(24)(25)(26)(27)(28), the veto cell phenomenon first described by Miller and associates (29)(30)(31)(32)(33)(34)(35)(36), and the concept of peripheral tolerance as opposed to tolerance induced by intrathymic clonal deletion ofantigen-reactive T lymphocytes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) to active suppression, but due to clonal paralysis of antigenreactive Lyt-2+ CTIrp-and 11,2-producing Lyt-2+ T cells . Since donor lymphocytes exhibit clonal anergy to recipient class I MHC antigens, yet express in vitro remarkably efficient veto functions, we believe that the reciprocal peripheral tolerance in the adult chimeric mice is caused, and maintained, by veto activity of donor and recipient cells.…”

“…In the model system ofneonatal tolerance, removal ofdonorderived cells revealed the existence of anti-donor-reactive T cells (10,11,51) . No evidence for active suppression was obtained in the model system detailed here (Table 4).…”

“…This conversion is successful in neonates: introduction of foreign antigens into a developing immune system prevents the system from responding further on to these antigens (1,2). Recent evidence indicates that both in natural tolerance and in experimentally induced neonatal unresponsiveness maturing antigen-reactive thymocytes become either clonally deleted (3)(4)(5)(6)(7)(8) or at least clonally silenced (9)(10)(11) .…”

Presence of Host‐Reactive and MHC‐Restricted T Cells in a Transplanted Severe Combined Immunodeficient (SCID) Patient Suggest Positive Selection and Absence of Clonal Deletion

“…Furthermore, in frog head-to-tail chimeras the bone marrow-derived T cells are not tolerant to the cells of the thymic donor in vitro but nevertheless accept skin graft (Flajnik et al 1985). In mice from some strains that are neonatally tolerant to class I MHC antigen, high frequencies of precursors of CTL that can recognize tolerogen were observed while, in vivo, prolonged graft survival was manifest (Heeg & Wagner 1985, Stockinger 1984. Several explanations can be envisioned for the apparent in vivo tolerance in the transplanted SCID patient SP.…”