Irreversible inactivation of activated cytotoxic T lymphocyte precursor cells by “anti‐self” suppressor cells present in murine bone marrow T cell colonies

Abstract

When added to a mixed lymphocyte culture, cells in T cell colonies grown from bone marrow (BM) suppressed the development of cytotoxic activity against H-2 antigens shared by the colony cells and the stimulator cells, apparently by inactivating cytotoxic T lymphocyte precursor cells (CTLP). From the point of view of the added suppressor cells, the suppression was against self-reactive cells. The suppressor cells were resistant to gamma irradiation (1500 rds) but sensitive to UV irradiation. Inactivated CTLP separated from the suppressor cells by cell sorting could not be reactivated on being recultured with fresh stimulator cells, suggesting the suppression is irreversible. There was a critical time window, extending roughly from 20 to 40 h after culture initiation, during which the suppressor cell had to be present if CTLP were to be inactivated. During the first 20 h and after 40 h of exposure to stimulator cells, CTLP were resistant to the suppressor cell. Direct experimental evidence is presented against the possibility that the suppressor cells derived from BM colonies act by augmenting the production of Lyt-2+ suppressor cells from the responder population which then produce the suppression, or that the suppressor cells interfere with an early interaction between CTLP and stimulator cells. We conclude that the suppressor cells in T cell colonies grown from BM act directly on activated CTLP and permanently inactivate them.

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.…”

“…Independently, Miller, Bevan, and associates (29)(30)(31)(32)(33)(34)(35)(36) pioneered the veto cell concept . Accordingly, unlinked to the specificity of their own antigen receptor, veto cells paralyze in vitro the response of T cells reacting to antigens displayed by the veto cells (29)(30)(31)(32)(33)(34)(35)(36) .…”

Rapamycin Prolongs Susceptibility of Responding T Cells to Tolerance Induction by CD8+ Veto Cells

“…However, it is unclear from these data if rapamycin alters the duration of susceptibility of a responding T cell to veto. Because mature CTL are not susceptible to veto-based deletion (13), and rapamycin inhibits T cell differentiation (1), we hypothesized that rapamycin would prevent T cells from differentiating out of a vetoable phenotype. To test this hypothesis, 2C anti-BALB/c MLRs were set up in the absence or presence of rapamycin and allowed to react for 3 days, during which time 2C cells cultured without rapamycin mature into CTL (as demonstrated in Fig.…”

“…One limitation of veto cell immunotherapy is that only CTL-p are susceptible to veto-based deletion, as veto cells delete neither naïve CD8 ϩ T cells nor fully mature effector cytolytic T lymphocytes (CTL) (13,14). Thus, there is a relatively narrow window during which veto cells can be used to condition the immune response of an organ transplant recipient.…”

Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34+ cells

“…No inhibition was detected when CD34 ϩ cells were added on day 2 or later. Thus, the veto effect of CD34 ϩ cells, similar to that of other veto cells, [21][22][23][24] acts in the early induction phase of allogeneic CTLs.…”