Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice.
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.
Ishida
Daisuke
D
Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Japan.
Yang
Hailin
H
Masuda
Kyoko
K
Uesugi
Kanami
K
Kawamoto
Hiroshi
H
Hattori
Masakazu
M
Minato
Nagahiro
N
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D017635:Clonal Anergy; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins; D007156:Immunologic Memory; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C091108:Sipa1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins