RESUMO
The persistence of memory T lymphocytes confers lifelong protection from pathogens. Memory T cells survive and undergo homeostatic proliferation (HSP) in the absence of Ag, although the cell-intrinsic mechanisms by which cytokines drive the HSP of memory T cells are not well understood. In this study we report that lysosome stability limits the long-term maintenance of memory CD8(+) T cell populations. Serine protease inhibitor (Spi) 2A, 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. Spi2A-deficient Ag-specific CD8(+) T cell populations declined more than wild-type competitors after viral infection, and they 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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Catepsina B/fisiologia , Memória Imunológica , Animais , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/metabolismo , Catepsina B/antagonistas & inibidores , Catepsina B/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Proliferação de Células , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Feminino , Homeostase/genética , Homeostase/imunologia , Memória Imunológica/genética , Lisossomos/enzimologia , Lisossomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Transgênicos , Serpinas/deficiência , Serpinas/fisiologiaRESUMO
The role played by apoptosis in the homeostasis of effector cells of the innate immune system is unclear. Serine protease inhibitor 6 (Spi6) is an inhibitor of granzyme B (GrB) that protects cytotoxic T lymphocytes of the adaptive immune system from apoptosis. To determine whether Spi6 also protects cells of the innate immune system from self-inflicted damage we have examined invariant NKT (iNKT) cells. Spi6-deficient iNKT cells harbored increased levels of GrB after TCR stimulation with the PBS-57 glycolipid Ag and were susceptible to apoptosis. The increased apoptosis of Spi6 knock-out (KO) iNKT cells lead to a complete loss in the production of IL-4 and IFN-gamma by Spi6 KO iNKT cells after PBS-57 challenge. The increased activation-induced apoptosis resulted in impaired survival and a decreased clonal burst size of Spi6 KO iNKT cells, which could be corrected by GrB deficiency. However, the clonal burst of Spi6 KO iNKT cells after TCR-independent activation with lymphocytic choriomeningitis virus was not affected. Our findings demonstrate that Spi6 protects cytotoxic cells of the innate immune system from GrB-mediated self-inflicted triggered by the recognition of Ag.