We studied the effects of the indirect pathway of allograft recognition using T cells from TCR transgenic Marilyn mice, which recognize the male Ag H-Y in an I-Ab-restricted fashion. The T cells are not alloreactive to the H-2k haplotype, because they are not activated when adoptively transferred into recombinase-activating gene-2−/− common γ-chain−/− double-mutant H-2k male or female mice. However, skin from H-2k males, but not from H-2k females, is acutely rejected by recombinase-activating gene-2−/− transgenic female recipients. In vitro, Marylin spleen cells primed by H-2k skin grafting proliferated and secreted both IL-4 and IFN-γ in response to H-2k male stimulators. However, the removal of H-2b APC from the responding population abolished the response. Taken together, these results show that the indirect recognition that triggers rejection in this model is due to the recognition of H-Y Ag shed from H-2k male allograft and presented by the recipient’s own I-Ab APC to transgenic T cells. This study demonstrates unequivocally the capacity of naive CD4+ T cells to promote the rejection of allografts through mechanisms that involve indirect destruction of grafted tissues.
The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4+ TCRBV8+ T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN-γ secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4+ T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4+CD25+ splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4+CD25− T regulatory cells prevented SEB-induced death independently of CD4+CD25+ T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25+ cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4+CD25+ T regulatory cells are required for the induction of SAg-induced tolerance, CD4+CD25− T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.
Mice made unresponsive by repeated injection of staphylococcal enterotoxin B (SEB) contained SEB-specific CD25+CD4+TCRBV8+ T cells that were able to transfer their state of unresponsiveness to primary-stimulated T cells. About one-half of these cells stably up-regulated the expression of CD152. We undertook the present study to determine whether CD152high cells seen in this system were T regulatory cells responsible for suppression or whether they represented SEB-activated CD4+ T effector cells. Our results show that, among SEB-specific TCRBV8+ T cells isolated from unresponsive mice, all CD152highCD25+CD4+ T cells expressed Foxp3, the NF required for differentiation and function of natural T regulatory cells. Moreover, suppression by CD25+CD4+TCRBV8+ T cells was fully inhibited by anti-CD152 Abs. Following stimulation by soluble CD152-Ig, dendritic cells (DC) isolated from unresponsive mice strongly increased the expression and the function of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for the catabolism of tryptophan. This capacity to activate IDO was independent of IFN-γ production by DC because CD152-Ig stimulation of DC isolated from SEB-treated IFN-γ-deficient animals activated IDO expression and function. Finally, adding 1-methyl-tryptophan, an inhibitor of tryptophan catabolism, increased substantially the capacity of DC from unresponsive animals to stimulate primary T cell response toward SEB. Thus, we conclude that IFN-γ-independent CD152-mediated activation of tryptophan catabolism by Foxp3+CD25+ T regulatory cells provides DC with immune regulatory activity in mice unresponsive to SEB.
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