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A Role for the Granzyme B Inhibitor Serine Protease Inhibitor 6 in CD8⁺ Memory Cell Homeostasis¹

Tiphanie Phillips^*, Joseph T. Opferman^2,*, Ramila Shah^*, Ni Liu^*, Christopher J. Froelich and Philip G. Ashton-Rickardt^3,*

^* Committees on Immunology and Developmental Biology, Department of Pathology, Ben May Institute for Cancer Research, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637; and Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201

Generation and maintenance of protective immunological memory is the goal of vaccination programs. It has recently become clear that CD8⁺ memory T cells are derived directly from CTLs. The mechanisms underlying this transformation and the subsequent survival of memory cells are not completely understood. However, some effector molecules required by CTLs to eliminate infected cells have also been shown to control the number of Ag-specific cells. We report that memory cells express high levels of serine protease inhibitor (Spi) 6, an inhibitor of the effector molecule granzyme B, and that Spi6 can protect T cells from granzyme B-mediated apoptosis. In mouse models, both elevated expression of Spi6 and the complete absence of granzyme B in CD8⁺ T cells led to an increase in memory cells after infection with lymphocytic choriomeningitis virus. This was not the result of increased levels of antilymphocytic choriomeningitis virus CD8⁺ T cells during the expansion or contraction phases, but rather transgenic Spi6 directly influenced the survival of CD8⁺ memory T cells. We propose that expression of protective molecules, like Spi6, serves to shield metabolically active CD8⁺ memory T cells from their own effector molecules.

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