4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells.
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 CD8 T cells in a subfraction of donors, whereas HIV-specific CTL from all donors exhibited a limited repertoire of effector functions. CD137L (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 TNFR-associated factor 1 in T cells using small interfering RNA resulted in increased levels of Bim in the 4-1BBL-stimulated T cells. Thus, costimulation via 4-1BBL leads to TNFR-associated factor 1-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.
Department of Immunology, University of Toronto, Toronto, Canada.
Chao
C
Wang
Tao
T
Wen
Jean-Pierre
JP
Routy
Nicole F
NF
Bernard
Rafick P
RP
Sekaly
Tania H
TH
Watts
D053330:4-1BB Ligand / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053282:CD27 Ligand / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D006678:HIV / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D047990:TNF Receptor-Associated Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism
D053330:4-1BB Ligand; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D053282:CD27 Ligand; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D047990:TNF Receptor-Associated Factor 1; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14