Evidence of alternative or concomitant use of perforin- and Fas-dependent pathways in a T cell-mediated negative regulation of Ig production

(T)o study the possible involvement of perforin (Pfp)- and/or Fas-dependent cytotoxicity pathways in a T cell-mediated negative regulation of Ig produ ction, we used the T cell-induced Ig-allotype suppression model. T splenocy tes from Igh(a/a) mice, when neonatally transferred into histocompatible Ig h(a/a) F-1 or Igh(b/b) congenic hosts, are intrinsically able to totally, s pecifically, and chronically suppress the production of IgG(2a) of the Igh( b) haplotype (IgG(2a)(b)). It has not been established whether the suppress ion effecters, which are anti-IgG(2a)(b) MHC class I-restricted CD8(+) T ce lls, cytolyse IgG(2a)(b+) B targets or whether they only silence Ig product ion. In this study, using T cells from Igh(a/a) Pfp(+/+) or Pfp(o/o) mice, the latter obtained by crossbreeding, and B cells from Igh(b/b) Fas(+/+) or Fas(Ipr/Ipr) (lymphoproliferation) mice in appropriate adoptive transfer m odels, we demonstrated that: 1) under blockage of the Pfp-mediated pathway, Igh(a/a) T cells were still able to induce suppression against wild-type I gG(2a)(b+) B cells, 2) IgG(2a)(b+) B cells with impaired Fas expression wer e also subjected to suppression by WT Igh(a/a) T splenocytes, and 3) the su ppression establishment was totally inhibited when both Pfp- and Fas-depend ent mechanisms were simultaneously blocked, i.e., when Igh(a/a) Pfp(o/o) T cells were used to induce suppression against Igh(b/b) FaS(Ipr/lpr) B cells . These results provide the first demonstration of the existence of alterna tive or simultaneous use of the major cytotoxic mechanisms in a T cell-medi ated down-regulation of an Ig production.