Requirements for serine protease inhibitor 2A (SPI2A) in the self-renewal of CD8+memory T cells and hematopoietic stem cells

Memory CD8+ T lymphocyte populations must persist for life to confer immunity to subsequent infections. Successful self-renewal requires both survival and homeostatic proliferation, while retaining the ability to proliferate and resume effector functions upon future challenges. Previous work has shown that Serine Protease Inhibitor 2A (Spi2A) ( Serpina3g), an anti-apoptotic cathepsin inhibitor, is upregulated in activated CD8+ T cells, and can protect them from the lysosomal pathway of programmed cell death. Furthermore, memory CD8+ T cells continue to express Spi2A long after infection. Memory CD8 + T cells have been postulated to share a similar self-renewal program of gene expression as long-term hematopoietic stem cells (HSC), which must also persist for life and respond to lymphopenic challenge. Long-term HSC also express Spi2A, but downregulate it upon differentiation to short-term HSC.;To examine the requirements for Spi2A in the self-renewal of memory CD8 + T cells and HSC, a Spi2A-deficient mouse model was generated. Spi2A KO mice developed a reduced amount of memory-phenotype CD44hi CD8+ T cells and antigen-specific memory CD8+ T cells. Spi2A-deficient antigen-specific CD8+ T cells, when transferred into recipient mice, developed a smaller proportion of memory CD8+ T cells after infection compared to wild type counterparts. These deficiencies corresponded with reduced homeostatic proliferation, and were rescued in mice lacking both Spi2A and Cathepsin B. Likewise, Spi2A KO mice developed a reduced amount of long-term HSC, also accompanied by reduced homeostatic proliferation, and rescued in mice lacking both Spi2A and Cathepsin B. Spi2A-deficient HSC, when transplanted into irradiated hosts, were less able to reconstitute blood development or the HSC compartment.;In contrast to previous results, Spi2A was not required to protect CD8 + T cells from supraoptimal TCR activation-induced cell death in vitro, even though this death was cathepsin-dependent. This discrepancy may be caused by redundant expression of Serpina3g and the homologous Serpina3f gene. However, Spi2A was required for the cytokine-induced survival of CD44hi CD8+ T cells and HSC.;Like HSC, the self-renewal of memory CD8+ T cells is supported by cytokine signals in the bone marrow. This shared program of self-renewal may be conferred by similar bone marrow niche microenvironments. The discovery of such a common mechanism may mean that therapeutic strategies to enhance the self-renewal of one may benefit the other.