The STING of death in T cells: IFN responses and cell death result from activation of T cell STING
Abstract: STING, a
critical mediator of IFN-I responses, has increasingly been recognized for its
importance in a variety of immune responses to intracellular bacterial and viral DNA as
well as endogenous DNA involved in tumorigenesis and the development of autoimmune
disease. Therapeutically, STING has also been proven to be a potent vaccine adjuvant for
model and tumor antigens. Yet, in all... read moreof these contexts STING has primarily been studied
for its role in innate immune activation of macrophages and dendritic cells. We present
here the first evidence of STING activation in T cells, resulting in IFN-I production
and increased ISG expression—responses that largely mirror the outcome of STING
activation in innate cells. In addition, we identify T cell-specific responses to STING
activation: unlike in macrophages and dendritic cells, T cells exhibit dramatic
increases in cell stress response and proapoptotic pathways that ultimately result in
cell death. These results may prompt a re-evaluation of the therapeutic uses of STING
agonists, as they could cause unrecognized damage to the T cell compartment. Conversely,
our findings suggest STING-based therapies may be beneficial for treating T cell
lymphoproliferative disorders, T cell lymphomas, and T cell-based transplant rejection
while sparing other immune system components.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Immunology.
Advisor: Alexander Poltorak.
Committee: Stephen Bunnell, Brigitte Huber, and Henry Wortis.
Keyword: Immunology.read less