Alloprimed CD8+ T Cells Regulate Alloantibody and Eliminate Alloprimed B Cells Through Perforin- and FasL-Dependent Mechanisms

Abstract

While it is well known that CD4+ T cells and B cells collaborate for antibody production, our group previously reported that CD8+ T cells downregulate alloantibody responses following transplantation. However, the exact mechanism involved in CD8+ T cell-mediated downregulation of alloantibody remains unclear. We also reported that alloantibody production is enhanced when either perforin or FasL is deficient in transplant recipients. Here, we report that CD8+ T cell-deficient transplant recipient mice (high alloantibody producers) exhibit an increased number of primed B cells compared to wild-type transplant recipients. Furthermore, CD8+ T cells require FasL, perforin, and allospecificity to downregulate posttransplant alloantibody production. In vivo CD8-mediated clearance of alloprimed B cells was also FasL- and perforin-dependent. In vitro data demonstrated that recipient CD8+ T cells directly induce apoptosis of alloprimed IgG1+ B cells in co-culture in an allospecific and MHC class I-dependent fashion. Altogether these data are consistent with the interpretation that CD8+ T cells downregulate posttransplant alloantibody production by FasL- and perforin-dependent direct elimination of alloprimed IgG1+ B cells.

Critical Role of NKT Cells in Posttransplant Alloantibody Production

“…We and others have shown that depletion of CD8 + T cells significantly increased antigen-specific antibody production in allergy, bacterial infection, viral infection, and platelet transfusion (15, 44-52). We reported a dominance of IgG1 alloantibody produced in CD8-deficient recipients (14) (confirmed in the current studies) but which differ from a report by Sayeh et al .…”

“…Using a well characterized in vivo model of posttransplant alloantibody production, we provided first evidence supporting a pivotal role for IFN-γ + CD8 + T cells in the inhibition of posttransplant IgG1 (IL-4-dependent) alloantibody production, in part, by downregulating the development of IL-4 + CD4 + T cells (14) and, in part, by killing IgG1 + B cells (15). Our data raise the possibility that current agents suppress T cell immune pathways which both promote (CD4 + T cells) and downregulate (CD8 + T cells) alloantibody production.…”

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

“…When CD8-depletion occurs prior to transplant and continues posttransplant, this prevents development of CD8 + allo-CTLs and also leads to a heightened alloantibody response 41 . Under these conditions transplanted hepatocytes are rejected rapidly in CD8-depleted WT recipients (MST=day 14) 26,27,33 .…”

“…Despite the spleen being an important immune locale of alloantibody-producing B cells 41,42 , the spleen is not required for alloantibody production as this pattern of alloantibody production in WT (titer=75±14) and absence of alloantibody production in LTα KO (titer=9±1) recipient groups persisted even after splenectomy. CD4 + T cell depletion of WT recipients, as expected, completely inhibited alloantibody production (titer=12±2).…”

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

“…Alternatively, the CD8 T cells could directly restrict the magnitude of the antibody response at early times post-transplant by interfering with the activities of helper T cells or B cells or eliminating these cell populations, possibly through cytotoxic mechanisms. Many studies have demonstrated the CD8 T cell mediated regulation of antibody responses to various antigens, including to allogeneic hepatocytes transplanted within the recipient spleen through cytolytic elimination of recipient B cells (30–33). …”