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

Abstract

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.

Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

“…This corroborates a recent study that reported that PD-1 -expressing cells comprise only a subpopulation of dysfunctional HIV-1 -specifi c CD8 + T cells in chronic progressors ( 52 ). The mechanisms leading to T cell exhaustion in the context of HIV-1 infection are clearly complex and cannot be attributed to a single pathway.…”

The capacity of the TNF family members 4‐1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells

“…Neither costimulatory TNF members nor ICOSL can be detected on the surface of these cells (our unpublished results) and there are in vitro data showing that human DC engineered to express TNF family ligands might induce efficient T-cell responses [33,34]. Cooperative effects between different costimulatory TNFR molecules have been demonstrated in animal models and on virus-specific human T cells [11,25,35] and we show here that proliferative responses to stimulation in the presence of high levels of 4-1BBL can be further enhanced by the B7 family member ICOSL but also the TNF family member CD70. Thus expressing 4-1BBL or combinations of 4-1BBL with other potent costimulatory molecules identified in this study might enhance the ability of DC-based cancer vaccines to induce efficient immune responses to tumours.…”

Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary

“…Additionally, the death of activated T cells is driven by the stimulation of a subset of TNF receptor family members including Fas, DR, and TRAIL. 47 …”