Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection.

Abstract

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.

• Authors: Chao Wang, Ann J McPherson, R Brad Jones, Kim S Kawamura, Gloria H Y Lin, Philipp A Lang, Thanuja Ambagala, Marc Pellegrini, Thomas Calzascia, Nasra Aidarus, Alisha R Elford, Feng Yun Yue, Elisabeth Kremmer, Colin M Kovacs, Erika Benko, Cecile Tremblay, Jean-Pierre Routy, Nicole F Bernard, Mario A Ostrowski, Pamela S Ohashi, Tania H Watts
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 209 Issue 1 Pg. 77-91 (Jan 16 2012) ISSN: 1540-9538 [Electronic] United States
• PMID: 22184633 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-1BB Ligand
• Antibodies
• Interleukin-7
• Programmed Cell Death 1 Receptor
• TNF Receptor-Associated Factor 1
• Transforming Growth Factor beta
• Chloroquine

Topics

• 4-1BB Ligand (immunology, metabolism)
• Adoptive Transfer
• Animals
• Antibodies (immunology, pharmacology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Chloroquine (pharmacology)
• Chronic Disease
• Down-Regulation (genetics)
• Gene Expression
• HIV Infections (genetics, immunology)
• Humans
• Immunologic Memory
• Interleukin-7 (pharmacology)
• Lymphocytic Choriomeningitis (genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Programmed Cell Death 1 Receptor (metabolism)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Factor 1 (deficiency, genetics)
• Transforming Growth Factor beta (metabolism)
• Viral Load (immunology)