Committees on Immunology and Developmental Biology, Department of Pathology, Ben May Institute for Cancer Research and Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, 924 East 57th Street, Chicago, Illinois 60637, USA.
An essential event in the development of memory CD8(+) T lymphocytes is the escape of progenitors from programmed cell death, but how this is mediated is unclear. Here we report that the gene encoding serine protease inhibitor 2A (Spi2A), an inhibitor of lysosomal executioner proteases dependent on transcription factor NF-kappaB, is upregulated in memory cell precursors. Spi2A upregulation protected lymphocytic choriomeningitis virus-specific memory progenitors from programmed cell death. Thus, Spi2A promotes the survival of cytotoxic T lymphocytes, allowing them to differentiate into memory CD8 T cells. These findings suggest a model in which commitment to the memory lineage is facilitated by the upregulation of protective genes.
"This determination was based on the downregulation of genes such as granzyme and perforin, which are the key cytotoxic proteins used by CTLs to kill their targets (Curtsinger et al. 2003; Mescher et al. 2006). A serine protease inhibitor Spi2a (Serpina3g), which has been implicated in aiding memory CTL formation (Liu et al. 2004), was upregulated. This means that rapamycin may also regulate memory-related genes like Spi2a directly. "
[Show abstract][Hide abstract] ABSTRACT: Memory programming of cytotoxic T cells (CTLs) by inflammatory cytokines can be regulated by mammalian target of rapamycin (mTOR). We have shown that inhibition of mTOR during CTL activation leads to the enhancement of memory, but the molecular mechanisms remain largely unknown. Using high-throughput RNA-Seq, we identified genes and functions in mouse CTLs affected by mTOR inhibition through rapamycin. Of the 43,221 identified transcripts, 184 transcripts were differentially expressed after rapamycin treatment, corresponding to 128 annotated genes. Of these genes, 114 were downregulated and only 14 were upregulated. Most importantly, 50 of them are directly related to cell death and survival. In addition, several genes such as CD62L are related to migration. Furthermore, we predicted downregulation of transcriptional regulators based on the total differentially expressed genes, as well as the subset of apoptosis-related genes. Quantitative PCR confirmed the differential expressions detected in RNA-Seq. We conclude that the regulatory function of rapamycin may work through inhibition of multiple genes related to apoptosis and migration, which enhance CTL survival into memory.
"Homology searches with AtSerpin1 sequence showed it to be most similar to vertebrate intracellular Clade B serpins (Fluhr et al., 2011) that monitor intracellular protease activity released from lysosomes (Silverman et al., 2004). For example, the serpin Spi2A (serine protease inhibitor 2A) promotes the survival of cytotoxic T lymphocytes by inhibiting executioner proteases released from the lysosome , thus allowing progenitors cells to differentiate into memory CD8 T-cells (Liu et al., 2004). In nematodes, the cytoplasmic localized serpin SRP-6 can inhibit calpains and lysosomal cysteine peptidases (cathepsins K, L, S and V). "
"KLRG1 hi IL-7R lo TE cells depend on IL-15 and there was also no defect in IL-2/15 receptor β chain expression in Stat3 −/− memory cells. Lastly, gene expression profiling revealed that Stat3 −/− CD8 + T cells expressed higher than normal amounts of Spi2A, another prosurvival factor for memory CD8 + T cells (Liu et al., 2004). Thus, it is possible that these factors combined account for the persistence of Stat3 −/− memory CD8 + T cells. "
[Show abstract][Hide abstract] ABSTRACT: Memory CD8(+) T cells are critical for long-term immunity, but the genetic pathways governing their formation remain poorly defined. This study shows that the IL-10-IL-21-STAT3 pathway is critical for memory CD8(+) T cell development after acute LCMV infection. In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8(+) T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central memory T cells. Expression of Eomes, BCL-6, Blimp-1, and SOCS3 was considerably reduced in STAT3-deficient memory CD8(+) T cells, and BCL-6- or SOCS3-deficient CD8(+) T cells also had perturbed memory cell development. Reduced SOCS3 expression rendered STAT3-deficient CD8(+) T cells hyperresponsive to IL-12, suggesting that the STAT3-SOCS3 pathway helps to insulate memory precursor cells from inflammatory cytokines that drive TE differentiation. Thus, memory CD8(+) T cell precursor maturation is an active process dependent on IL-10-IL-21-STAT3 signaling.
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