Mice naturally tolerant to C5 have T cells that suppress the response to this antigen

Abstract

We examined whether C5-sufficient mice which are naturally tolerant to this antigen have suppressor T cells to C5 humoral immune response. Two congenic strains of mice B10.D2 (NSN) and B10.D2 (OSN) differing only in the presence or absence of C5 were used. Irradiated (760 rds) sufficient hosts were reconstituted with a nonadherent spleen cell suspension from either sufficient or deficient mice or a mixture of both. Hemolytic C5 levels were assayed. Sufficient spleen cells appeared to prevent the drop of C5 level caused by anti-C5 antibody made by deficient spleen cells. Spleen cell suspensions from sufficient mice primed with deficient spleen cells exhibited better anti-C5 activity than normal sufficient spleen cell suspensions. This anti-C5 activity is abrogated by treatment of the NSN spleen cell suspensions obtained from NSN primed with OSN spleen cells with anti-Thy-1.2 antiserum and complement. Suppression of the humoral response to C5 failed to affect the anti-sheep red blood cell immune response. Suppressor T cells are resistant to low-dose irradiation, cortisone treatment and adult thymectomy. In contrast, they are sensitive to high doses of irradiation and both high and low doses of cyclophosphamide treatment. Thus, C5-sufficient mice, in contrast to C5-deficient mice, appear to have antigen-specific suppressor T cells which downregulate the humoral immune response to C5. In addition, we examined the relationship of these suppressor T cells to the state of tolerance in helper T cells of C5-sufficient mice. This was done in irradiated deficient mice which were repopulated with spleen cell suspensions selectively depleted of either Lyt-1+ or Lyt-2+ T cell subsets. These chimeras were challenged with murine C5 and both the primary and secondary immune response was measured by inhibition of the C5 hemolytic activity. It was found that only spleen cell suspensions of the deficient mice selectively depleted from the Lyt-2+ subset of T cells responded to the antigen both in the primary and secondary response. In contrast, either subset of T cells from the sufficient mice failed to respond. Thus, it appears that in sufficient mice helper T cells to C5 are intrinsically tolerant or physically and/or functionally deleted. In conclusion, the data suggest that both T cell compartments are unresponsive and play a role in the mechanism of tolerance to a physiologic antigen.

Regulatory T cells essential to prevent the loss of self-tolerance in murine models of erythrocyte-specific autoantibody responses

“…There have been numerous demonstrations, as early as the 1970s and 1980s, that self-reactive cells exist in normal, non-autoimmune mice [59,[77][78][79][80][81][82][83][84][85]. Many of these demonstrations involved removing the reactive cells from their normal environment, implying the existence in that environment of peripheral control mechanisms.…”

“…Many of these demonstrations involved removing the reactive cells from their normal environment, implying the existence in that environment of peripheral control mechanisms. Regulatory T-cell populations have been demonstrated in many of these models to abrogate the development of autoimmune diabetes [77,78], thyroiditis, [79], experimental allergic encephalomyelitis [EAE; 80,81], gastritis and orchitis [59,82,83], nephritis [84], autoantibody responses to the C5 component of complement [85], and autoantibody production by DNA-specific B-cell lines [86]. Some of these studies identified the cells responsible for control as CD8 ?…”

“…Some of these studies identified the cells responsible for control as CD8 ? suppressor T cells [80,81,85] and some as CD4 ? Tregs [59,78,82,83].…”

The Physiological Role of Regulatory T Cells in the Prevention of Autoimmunity: the Function of the Thymus in the Generation of the Regulatory T Cell Subset

“…In T and B cell mixing experiments from the two strains, it was shown that B cells from either strain had the potential for anti-C5 reactivity and that the tolerance to C5 was strictly T cell dependent. Evidence for a population of T cells able to inhibit a response to C5 was demonstrated by Cairns et al (1986). It was found that non-adherent spleen cells (naSC) from C5~ animals, upon adoptive transfer to sublethally irradiated C5"^ animals, were able to make an antibody response to C5, resulting in a transient, but significant, reduction in C5 levels.…”

“…Given that T cell anergy is a reversible state (Mueller et al 1989) this explanation cannot entirely be dismissed. However in the dominant tolerance in which antigen specificity is known, for example in the thymus transplantation experiments of Coutinho et al (1993) and Zamoyska et al (1989) and in the C5 experiments of Cairns et al (1986), it is difficult to refute the view that the T cells that mediate dominant tolerance are specific for the "tolerated" antigen. While in principle the observed antigen specificity could arise through the recognition, by the regulatory T cells, of the TCR idiotypes on the regulated cells the existence of such a mechanism would impose an enormous extra burden on the intrathymic selection of the T cell repertoire.…”