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4‐1BBL is a critical component in the costimulation dependent rescue of functionally impaired HIV‐specific CTL
Author(s) -
Wang Chao,
Wen Tao,
Routy JeanPierre,
Bernard Nicole,
Sekaly Rafick,
Watts Tania
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.663.1
Subject(s) - ctl* , cd80 , cytotoxic t cell , cd8 , cd28 , population , immunology , immune system , t cell , biology , microbiology and biotechnology , cd40 , medicine , in vitro , genetics , environmental health
During chronic infection, HIV‐specific CD8 T cells exhibit progressive signs of functional impairment, attributed to persistent antigenic stimulation, up‐regulation of the inhibitory receptor PD‐1, and declining T cell help. Strategies that directly improve CD8 T cell function offer the potential of restoring immune control of HIV. Although PD‐1 expression has been identified as a cause of functional impairment in HIV, in this study, PD‐1 expression was observed on only a subfraction of HIV‐specific CTL in a subfraction of donors, whereas HIV‐specific CTL from all donors exhibited a limited repertoire of effector functions. 4‐1BBL is emerging as an important stimulator of antiviral CD8 T cell responses. Regardless of the PD‐1 status of the donors, here we show that 4‐1BBL, when combined with CD80 or CD70, expands a population of Ag‐specific CD8 T cells expressing multiple markers of effector function, from the functionally impaired starting population. In contrast, CD70 in combination with CD80 was insufficient for these effects and the related TNF family ligand, LIGHT, had negligible activity. The unique contribution of 4‐1BBL correlated with down‐regulation of the proapoptotic molecule Bim in activated CD8 T cells. Decreasing the level of TRAF1 in T cells using siRNA resulted in increased levels of Bim in the 4‐1BBL‐stimulated CD8s. Thus, costimulation via 4‐1BBL leads to TRAF1‐dependent Bim down‐modulation in T cells, resulting in increased T cell expansion. These studies identify 4‐1BBL as a critical component in therapeutic strategies aimed at improving CD8 T cell function.