Evidence of Alternative or Concomitant Use of Perforin- and Fas-Dependent Pathways in a T Cell-Mediated Negative Regulation of Ig Production

Abstract

To study the possible involvement of perforin (Pfp)- and/or Fas-dependent cytotoxicity pathways in a T cell-mediated negative regulation of Ig production, we used the T cell-induced Ig-allotype suppression model. T splenocytes from Igha/a mice, when neonatally transferred into histocompatible Igha/b F1 or Ighb/b congenic hosts, are intrinsically able to totally, specifically, and chronically suppress the production of IgG2a of the Ighb haplotype (IgG2ab). It has not been established whether the suppression effectors, which are anti-IgG2ab MHC class I-restricted CD8+ T cells, cytolyse IgG2ab+ B targets or whether they only silence Ig production. In this study, using T cells from Igha/a Pfp+/+ or Pfpo/o mice, the latter obtained by crossbreeding, and B cells from Ighb/b Fas+/+ or Faslpr/lpr (lymphoproliferation) mice in appropriate adoptive transfer models, we demonstrated that: 1) under blockage of the Pfp-mediated pathway, Igha/a T cells were still able to induce suppression against wild-type IgG2ab+ B cells, 2) IgG2ab+ B cells with impaired Fas expression were also subjected to suppression by WT Igha/a T splenocytes, and 3) the suppression establishment was totally inhibited when both Pfp- and Fas-dependent mechanisms were simultaneously blocked, i.e., when Igha/a Pfpo/o T cells were used to induce suppression against Ighb/b Faslpr/lpr B cells. These results provide the first demonstration of the existence of alternative or simultaneous use of the major cytotoxic mechanisms in a T cell-mediated down-regulation of an Ig production.