Loss of the signaling adaptor TRAF1 causes CD8(+) T cell dysregulation during human and murine chronic infection
AuthorWang, C; McPherson, AJ; Jones, RB; Kawamura, KS; Lin, GHY; Lang, PA; Ambagala, T; Pellegrini, M; Calzascia, T; Aidarus, N; ...
Source TitleJournal of Experimental Medicine
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sPellegrini, Marc
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsWang, C., McPherson, A. J., Jones, R. B., Kawamura, K. S., Lin, G. H. Y., Lang, P. A., Ambagala, T., Pellegrini, M., Calzascia, T., Aidarus, N., Elford, A. R., Yue, F. Y., Kremmer, E., Kovacs, C. M., Benko, E., Tremblay, C., Routy, J. -P., Bernard, N. F., Ostrowski, M. A. ,... Watts, T. H. (2012). Loss of the signaling adaptor TRAF1 causes CD8(+) T cell dysregulation during human and murine chronic infection. JOURNAL OF EXPERIMENTAL MEDICINE, 209 (1), pp.77-91. https://doi.org/10.1084/jem.20110675.
Access StatusOpen Access
The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL-deficient mice have defects in viral control early, but not late, in chronic infection. TGFβ induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti-4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1(+) but not TRAF1(-) memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy.
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