Cathepsin B controls the persistence of memory CD8 + T lymphocytes

The persistence of memory T lymphocytes confers lifelong protection from pathogens. Memory T cells survive and undergo homeostatic proliferation (HSP) in the absence of antigen, although the cell intrinsic mechanisms by which cytokines drive the HSP of memory T cells are not well understood. We now report that lysosome stability limits the long-term maintenance of memory CD8(+) T cell populations. Serine protease inhibitor 2A (Spi2A), an anti-apoptotic cytosolic cathepsin inhibitor, is induced by both IL-15 and IL-7. Mice deficient in Spi2A developed fewer memory-phenotype CD44(hi) CD8(+) T cells with age, which underwent reduced HSP in the bone marrow. Spi2A was also required for the maintenance of central memory CD8(+) T cell populations after acute infection with Lymphocytic Choriomeningitis virus (LCMV). Spi2A-deficient antigen-specific CD8(+) T cell populations declined more than wild type competitors after viral infection, and were eroded further after successive infections. Spi2A protected memory cells from lysosomal breakdown by inhibiting cathepsin B. The impaired maintenance of Spi2A-deficient memory CD8(+) T cells was rescued by concomitant cathepsin B deficiency, demonstrating that cathepsin B was a physiological target of Spi2A in memory CD8(+) T cell survival. Our findings support a model in which protection from lysosomal rupture through cytokine-induced expression of Spi2A determines the long-term persistence of memory CD8(+) T cells