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Receptor Plays a Critical Role in T Cell Alloreactivity1
*
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
Mater Medical Research Institute, South Brisbane, Australia; and
Departments of Internal Medicine and Pediatrics, Bone Marrow Transplant Program, University of Michigan Cancer Center, MI 48109
TNF-
is known to be an important mediator of tissue damage
during allograft rejection and graft-vs-host disease (GVHD), but its
role in supporting T cell responses to allogeneic Ags is unclear. We
have studied this question by comparing normal mice with those lacking
the p55 (p55 TNFR-/-) or p75 (p75 TNFR-/-)
TNF- receptors as donors in well-defined bone marrow transplant
(BMT) models. Recipients of p55 TNFR-/- cells had
significantly reduced mortality and morbidity from GVHD compared with
the other two sources of T cells. In vitro, T cells lacking the p55
(but not the p75) TNF- receptor exhibited decreased proliferation
and production of Th1 cytokines in MLC. This defect was only partially
restored by exogenous IL-2 and affected both CD4+ and
CD8+ populations. CD8+ p55
TNFR-/- proliferation was impaired independently of IL-2
whereas CTL effector function was impaired in an IL-2-dependent
fashion. Inhibition of TNF- with TNFR:Fc in primary MLC also
impaired the proliferation and Th1 differentiation of wild-type T
cells. BMT mixing experiments demonstrated that the reduced ability of
p55 TNFR-/- donor cells to induce GVHD was due to the
absence of the p55 TNFR on T cells rather than bone marrow cells. These
data highlight the importance of TNF- in alloreactive T cell
responses and suggest that inhibition of the T cell p55 TNF-
receptor may provide an additional useful therapeutic maneuver to
inhibit alloreactive T cell responses following bone marrow and solid
organ transplantation.
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