Antigen-Driven T Cell Anergy and Defective Memory T Cell Response via Deregulated Rap1 Activation in SPA-1-Deficient Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 19; pp. 10919 - 10924
• Main Authors: Ishida, Daisuke, Yang, Hailin, Masuda, Kyoko, Uesugi, Kanami, Kawamoto, Hiroshi, Hattori, Masakazu, Minato, Nagahiro
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.09.2003; National Acad Sciences
• Subjects: Animals; Antibodies; Antigen presentation; Antigens; B lymphocytes; Biological Sciences; Cell Differentiation; Cells, Cultured; Clonal Anergy; Cultured cells; Enzyme Activation; GTPase-Activating Proteins; Immunologic Memory; Immunology; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Progenitor cells; rap1 GTP-Binding Proteins - metabolism; Rodents; Spleen cells; Stem cells; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes - immunology; Thymocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1834525100

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 CD44highT 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 CD44highT 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 naı̈ ve 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.