Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice

Daisuke Ishida, Hailin Yang, Kyoko Masuda, Kanami Uesugi, Hiroshi Kawamoto, Masakazu Hattori, Nagahiro Minato

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40 Citations (Scopus)


SPA-1 is a principal Rap1 GTPase-activating protein in the hematopoietic progenitors and peripheral T cells, and SPA-1-deficient mice develop a spectrum of myeloproliferative stem cell disorders of late onset. In the present study, we show that SPA-1-deficient mice develop age-dependent T cell unresponsiveness preceding the myeloid disorders, whereas the T cell numbers remained unchanged. Progression of the T cell dysfunction was attributed to the age-dependent increase in CD44high T cell population that was unresponsive to T cell receptor stimulation. Younger SPA-1-deficient mice exhibited selectively impaired recall T cell responses against a T-dependent antigen with normal primary antibody response. These results suggested that the unresponsiveness of CD44high T cells was antigen-driven in vivo. T cells from younger SPA-1-/- mice showed much greater and more persisted Rap1 activation by anti-CD3 stimulation than control T cells. Furthermore, freshly isolated T cells from SPA-1-/- mice exhibited progressive accumulation of Rap1GTP as mice aged. T cells from aged SPA-1-/- mice with high amounts of Rap1GTP showed normal or even enhanced Ras activation with little extracellular signal-regulated kinase activation in response to anti-CD3 stimulation, indicating that excess Rap1GTP induced the uncoupling of Ras-mediated extracellular signal-regulated kinase activation. These results suggested that antigenic activation of naïve T cells in SPA-1 -/- mice was followed by anergic rather than memory state due to the defective down-regulation of Rap1 activation, resulting in the age-dependent progression of overall T cell immunodeficiency.

Original languageEnglish
Pages (from-to)10919-10924
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
Publication statusPublished - 16-09-2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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