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The Journal of Immunology, 1999, 162: 1192-1199.
Copyright © 1999 by The American Association of Immunologists

A Role for Perforin in Activation-Induced T Cell Death In Vivo: Increased Expansion of Allogeneic Perforin-Deficient T Cells in SCID mice1

David Spaner1,*,{dagger}, Kaliannan Raju*, Brian Rabinovich* and Richard G. Miller*

* Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, and {dagger} Division of Cancer Biology Research, Sunnybrook Health Science Center, Toronto, Canada

Despite defective granule exocytosis, T cells from mice whose perforin gene was ablated by homologous recombination (pko mice) caused a similar degree of graft-vs-host disease as normal T cells after injection into sublethally irradiated C.B-17 SCID mice. Moreover host spleens contained significantly greater numbers of T cells from pko mice than from wild-type mice following their i.v. injection. This increase could not be explained by persistence of host APCs that were not cleared by defective donor cytotoxic effector cells. The absence of functional perforin-dependent suppressor cells or an altered cytokine profile of donor T cells could also not account for the behavior of pko cells. Spontaneous and Fas-mediated apoptosis of in vivo activated donor T cells were independent of donor origin. However, pko T blasts exhibited less growth inhibition and cell death after reactivation in vitro. The results are compatible with a model of a defective activation-induced cell death (AICD) pathway, controlled by perforin, accounting for the increased expansion of alloreactive pko T cells.




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