Masking of veto function in vivo by activated CD4⁺ T lymphocytes

Abstract

Donor CD8+ T lymphocytes injected into recipient mice incompatible at major histocompatibility complex (MHC) class I genes induce donor-specific CTL nonresponsiveness, attributed to the veto function of donor cells. Here we show that conditions leading to strong activation of CD4+ T cells, namely the presence in the recipient of foreign MHC class II determinants, lead to the apparent loss of veto function of donor cells. This "masking" of veto function is dependent on the dose of foreign MHC class II present. Veto function can be partially restored by treatment of recipients in vivo with CD4-specific antibody, a measure which has been shown to eliminate the function of CD4+ T cells in vivo. We conclude that CD4+ T cells activated by contact with antigen can interfere with the veto function of CD8+ T cells. Consequences of this finding are: (a) veto function of a sample cell population can be overlooked when activation of CD4+ T cells occurs simultaneously. (b) The balance between veto function of recipient cells and its abrogation might be responsible for the kind of graft-vs.-host reaction generated (CD8+ T cell-mediated and frequently lethal or CD4+ T cell-mediated and not lethal) when parental T cells are injected into recipients incompatible at MHC class I and class II genes. (c) A possible contribution of veto cells should be considered in several protocols in which donor hemopoetic cells were used in conjunction with CD4-specific antibodies to induce transplantation tolerance. (d) Veto function in vivo does not require a contribution of CD4+ T cells.

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.

“…5 ; Table 1) . Although establishment of tolerance to class I MHC antigens by pretransplant transfusion meets difficulties if the transfused allogeneic lymphocytes in addition are class II MHC incompatible (26,27, unpublished data), a problem that is overcome by systemic application of anti-L3T4 mAb (27), our data, in addition, imply that recipient L3T4+ cells are essential for the in vivo development of veto cell-dependent peripheral tolerance. Recipient L3T4+ T cells might interact with MHC class II-expressing donor veto cells directly, or might support the activation of veto functions by actively participating in the in vivo response to class I MHC antigens via lymphokine secretion .…”

“…Even though there are numerous indications that pretransplant transfusion can induce specific immunosuppression rather than sensitization (20)(21)(22)(23)(24)(25)(26)(27)(28), the results presented here provide compelling evidence that pretransplant transfusion-induced peripheral tolerance to class I MHC antigens is associated with the in vivo activation and selection ofremarkably efficient veto cells . Opposing thymic deletion of antigen-reactive T cells as a basis for negative selection of maturing T lymphocytes (4-8), veto cells operating in peripheral tolerance clonally appear to silence mature Lyt-2 * T cells.…”

“…Evaluation of pretransplant transfusion effects have indicated that intravenous confrontation with allogeneic cells may induce specific immunosuppression rather than sensitization (20)(21)(22)(23)(24)(25)(26)(27)(28) Miller, Bevan, 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 (29-36) .…”

“…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.…”

“…Therefore, most strategies attempt first to reduce the pool of immunocompetent peripheral T lymphocytes, and thereafter to induce unresponsiveness by exposing the regenerating (neonatal) immune system to antigen . In the first step, rather invasive techniques are used, such as whole body (15, 16) or total lymphoid irradiation (17), systemic application of antiproliferative drugs (18,19), or a combination of either of these methods.Evaluation of pretransplant transfusion effects have indicated that intravenous confrontation with allogeneic cells may induce specific immunosuppression rather than sensitization (20)(21)(22)(23)(24)(25)(26)(27)(28) Miller, Bevan, 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 (29-36) .…”