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: CD8+ Effector Cells Develop Independently of CD4+ Cells and CD40-CD40 Ligand Interactions1
*
Department of Surgery, Section of General Surgery, and Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109;
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; and
Department of Surgery, Division of Transplantation, Ohio State University School of Medicine, Columbus, OH 43210
Both wild-type (WT) and IFN-
-deficient
(IFN--/-) C57BL/6 mice can rapidly reject BALB/c
cardiac allografts. When depleted of CD8+ cells, both WT
and IFN--/- mice rejected their allografts, indicating
that these mice share a common CD4-mediated, CD8-independent mechanism
of rejection. However, when depleted of CD4+ cells, WT mice
accepted their allografts, while IFN--/- recipients
rapidly rejected them. Hence, IFN--/-, but not WT mice
developed an unusual CD8-mediated, CD4-independent, mechanism of
allograft rejection. Allograft rejection in IFN--/-
mice was associated with intragraft accumulation of IL-4-producing
cells, polymorphonuclear leukocytes, and eosinophils. Furthermore, this
form of rejection was resistant to treatment with anti-CD40 ligand
(CD40L) mAb, which markedly prolonged graft survival in WT mice. T cell
depletion studies verified that anti-CD40L treatment failed to
prevent CD8-mediated allograft rejection in IFN--/-
mice. However, anti-CD40L treatment did prevent CD4-mediated
rejection in IFN--/- mice, although grafts were
eventually rejected when CD8+ T cells repopulated the
periphery. The IL-4 production and eosinophil influx into the graft
that occurred during CD8-mediated rejection were apparently
epiphenomenal, since treatment with anti-IL-4 mAb blocked
intragraft accumulation of eosinophils, but did not interfere with
allograft rejection. These studies demonstrate that a novel,
CD8-mediated mechanism of allograft rejection, which is resistant to
experimental immunosuppression, can develop when IFN- is limiting.
An understanding of this mechanism is confounded by its association
with Th2-like immune events, which contribute unique histopathologic
features to the graft but are apparently unnecessary for the process of
allograft rejection.
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