CD40L-specific mAb mediates its tolerogenic effects through engagement of FcgRIIB, not via depletion of activated T cells (141.17)

Abstract

Abstract Objective: To determine the mechanism by which a widely used anti-mouse CD40L mAb (clone MR1) given with allogeneic bone marrow cells (BMCs) tolerizes peripheral CD8 T cells. Methods: B6 mice received 3Gy total body irradiation one day prior to ip injection of 2mg a-CD40L & iv infusion of 25x106 MHC-mismatched B10.A BMCs. This regimen induces long-term mixed chimerism, as measured by durable presence of donor leukocytes, without depletion of recipient CD4 or CD8 T cells. Results: Although genetic deficiency of CD40L alone allowed graft acceptance in recipients depleted of CD8 cells, it did not prevent rejection in mice replete with CD8 T cells. Thus, Fc-dependent functions of a-CD40L were studied. A role for complement was excluded, as 4/5 C3 KO recipients became chimeric. CD8 T cell-intrinsic CD40L was dispensable (3/5 chimeras each in mice with WT or KO CD8 cells), indicating that a-CD40L need not act directly on CD8 cells. However, FcgRIIB KO recipients promptly rejected donor BM unless CD8 T cells were depleted (5/7, 0/5, 7/8, & 5/7 chimeras for WT, KO, WT + a-CD8, & KO + a-CD8 groups, respectively). Recipient B cells are the likely source of FcgRIIB, as DC-derived FcgRIIB was not essential (4/6 chimeras each in mice with WT or KO DC). Conclusions: A-CD40L with allogeneic BMCs generates immune complexes that ligate FcgRIIB, inducing as yet undefined downstream effects essential for CD8 T cell tolerance. Supported by NIH Grant RO1 49915 & NDSEG Fellowship.