RELA tunes innate-like interferon I/III responses in human T cells

Abstract

In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.

Cell-free assays reveal the HIV-1 capsid protects reverse transcripts from cGAS

“…In the THP-1 case, and presumably also in primary myeloid cells, cGAS activation by reverse transcription products leads to innate immune activation via the canonical STING pathway. However, we have not yet identified conditions that lead to LEN-induced IFN production in CD4+ T cells, suggesting that additional host circuitry might be required to unleash this response in the main target cells of HIV 60,61 .…”

Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

“…Induction of these pathways is known to be a hallmark of HIV-1 infection in monocytes and macrophages, much more prominently than in T cells. 102 , 103 , 104 , 105 Thus, it is not surprising to have seen this strong response in microglia, which share many physiologic properties with macrophages (reviewed by Li and Barres 106 ). Most studies suggest that the interferon response is relatively transient; thus, the persistent expression in the microglial cell infection of at least a subset of ISGs may be a relatively unique feature of microglial HIV-1 infection that may have important pathophysiologic consequences.…”

BST2 regulated by the transcription factor STAT1 can promote metastasis, invasion and proliferation of oral squamous cell carcinoma via the AKT/ERK1/2 signaling pathway

“…Furthermore, it was hypothesized that STAT1 and BST2 are highly expressed in certain cancers where the local immune system where the tumor forms is damaged and, the tumor tissue forms tumor microenvironment with an altered immune system independent of the external environment. Since tumor cells are attacked by the body's immune system, the immune system within tumor tissue may be more active than that of normal tumor tissue (33). This may be a reason why the expression levels of the immune-related proteins STAT1 and BST2 are higher in OSCC than in normal tissues (34)(35)(36)(37).…”