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Serine protease inhibitor 2A is a protective factor for memory T cell development

Nature Immunology volume 5, pages 919–926 (2004)Cite this article

Abstract

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-κB, 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.

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Figure 1: Gene expression in CD8 T cell populations.
Figure 2: Spi2A expression and PCD in bone marrow chimeras.
Figure 3: Spi2A affects the number of LCMV-specific CD8 T cells.
Figure 4: Effect of cathepsin B inhibition on the CD8 T cell response to LCMV.
Figure 5: Spi2A facilitates the development of memory CD8 T cells.

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Acknowledgements

We thank R. Welsh for high-titer stocks of LCMV Armstrong; J. Marvin and R. Duggan for help with flow cytometry; and G. Franzoso and S. Byrne for comments. Supported by Medical Scientist Training Program (GM07281 to T.P.) and National Institutes of Health (AI45108 to P.G.A-R.)

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Author notes

  1. Joseph T Opferman

    Present address: Dana Farber Cancer Institute, Harvard University Medical School, 1 Jimmy Fund Way, Boston, Massachusetts, 02115, USA

Authors and Affiliations

  1. Department of Pathology, Committees on Immunology and Developmental Biology, Ben May Institute for Cancer Research and Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, 924 East 57th Street, Chicago, 60637, Illinois, USA

    Ni Liu, Tiphanie Phillips, Manling Zhang, Yue Wang, Joseph T Opferman, Ramila Shah & Philip G Ashton-Rickardt

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Correspondence to Philip G Ashton-Rickardt.

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Supplementary information

Supplementary Fig. 1

Expression of epitope-tagged Spi2A in BM chimeras. (PDF 98 kb)

Supplementary Fig. 2

Effect of Spi2A expression on the level of IL-7Rhi anti-LCMV CD8 T cells. (PDF 86 kb)

Supplementary Fig. 3

Effect of Spi2A on the level of IL-7R expression in anti-LCMV CD8 T cells. (PDF 66 kb)

Supplementary Fig. 4

Induction of Spi2A mRNA in CD8 T cells by IL-7 in vitro. (PDF 63 kb)

Supplementary Fig. 5

Inhibition of cathepsin B reduces PCD of anti-LCMV CD8 T cells in vitro. (PDF 78 kb)

Supplementary Fig. 6

Effect of CA-074 Me and Spi2A on cytoplasmic cathepsin B activity. (PDF 72 kb)

Supplementary Table 1

DNA 11kA array analysis of gene expression in B6.2.16 CD8 cells. (PDF 132 kb)

Supplementary Table 2

DNA 11kB array analysis of gene expression in B6.2.16 CD8 cells. (PDF 100 kb)

Supplementary Table 3

Relative Expression of Candidate genes in Memory compared to Naïve CD8 cells. (PDF 42 kb)

Supplementary Table 4

Generation of bone marrow chimeras transduced with retrovirus. (PDF 30 kb)

Supplementary Table 5

Levels of thymocytes in bone marrow chimeras transduced with retrovirus. (PDF 31 kb)

Supplementary Table 6

Levels of mature T cells in peripheral lymphoid organs of chimeras transduced with retrovirus. (PDF 33 kb)

Supplementary Methods (PDF 62 kb)

Supplementary Note 1 (PDF 74 kb)

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Liu, N., Phillips, T., Zhang, M. et al. Serine protease inhibitor 2A is a protective factor for memory T cell development. Nat Immunol 5, 919–926 (2004). https://doi.org/10.1038/ni1107

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