Common TMEM173 HAQ and AQ Alleles Prevent CD4 T Cell Death, Restore T-Regs, and Alleviate SAVI (N153S) Inflammatory Disease in Mice

Core Concepts

The common human TMEM173 alleles HAQ and AQ prevent STING-mediated CD4 T cell death, restore T-regulatory cells, and alleviate the inflammatory SAVI disease in mice.

Abstract

The study investigates the in vivo significance and mechanisms of STING-mediated CD4 T cell death, which has been implicated in various inflammatory diseases. Using STING knock-in mice expressing common human TMEM173 alleles HAQ, AQ, and Q293, the authors made several key findings: STING activation readily induces cell death in mouse splenocytes, including CD4 T cells, CD8 T cells, and B cells, in a TBK1-dependent manner. Surprisingly, splenocytes from HAQ, AQ, and Q293 mice are resistant to STING-mediated cell death ex vivo, indicating that the STING residue 293 is critical for this cell death function. In the SAVI (N153S) mouse model, the HAQ and AQ alleles prevent CD4 T cellpenia, increase/restore T-regulatory cells, and alleviate/stop tissue inflammation and mortality. The AQ/SAVI(N153S) mice have similar STING activation, TBK1-IRF3 and NF-κB signaling as the WT/SAVI(N153S) mice, suggesting that the canonical STING pathway is not sufficient for inducing cell death in vivo. The authors propose that STING activation promotes tissue inflammation by depleting T-regulatory cells, and the common HAQ and AQ alleles can prevent this STING-mediated CD4 T cell death mechanism. Overall, the study reveals the in vivo significance of the type I IFN-independent, STING-mediated CD4 T cell death pathway and its modulation by common human TMEM173 alleles, providing insights into STING-driven inflammatory diseases and potential implications for STING-targeted therapies.

Stats

The splenocytes from C57BL/6N mice treated with 100 ng/ml diABZI showed 70% cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice had 10-fold and 20-fold increased spleen T-regulatory cells compared to WT/SAVI mice, respectively.

Quotes

"Billions of modern humans have the dominant HAQ, AQ alleles. STING research and STING-targeting immunotherapy should consider TMEM173 heterogeneity in humans." "Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan."

Key Insights Distilled From

The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

by Aybar-Torrie... at www.biorxiv.org 10-07-2023

https://www.biorxiv.org/content/10.1101/2023.10.05.561109v2

Deeper Inquiries

How might the STING-mediated CD4 T cell death pathway be involved in other inflammatory diseases beyond SAVI, such as HIV infection or cancer immunotherapy?

The STING-mediated CD4 T cell death pathway could play a significant role in various inflammatory diseases beyond SAVI, including conditions like HIV infection and cancer immunotherapy. In the context of HIV infection, where the virus primarily targets CD4 T cells, the activation of the STING pathway in these cells could lead to their depletion. HIV-induced CD4 T cell death is a hallmark of untreated HIV infection, and the STING pathway may contribute to this process. By preventing STING-mediated CD4 T cell death, individuals with HAQ or AQ alleles may have a protective mechanism against the loss of CD4 T cells during HIV infection, potentially influencing disease progression and the development of AIDS. In cancer immunotherapy, where STING activation is being explored as a strategy to enhance anti-tumor immune responses, the STING-mediated CD4 T cell death pathway could have implications for treatment outcomes. While STING activation is intended to boost immune responses against cancer cells, excessive activation leading to CD4 T cell death could have detrimental effects on the overall immune response. Understanding how HAQ and AQ alleles prevent STING-induced CD4 T cell death could provide insights into optimizing cancer immunotherapy strategies to avoid unwanted immune cell depletion and enhance treatment efficacy.

What are the potential mechanisms by which the HAQ and AQ alleles specifically prevent STING-induced CD4 T cell death, but not the canonical STING signaling pathways?

The HAQ and AQ alleles exhibit a unique ability to prevent STING-induced CD4 T cell death while not interfering with the canonical STING signaling pathways. Several potential mechanisms could underlie this specific function of the HAQ and AQ alleles: Residue-specific effects: The HAQ and AQ alleles carry specific amino acid changes at residues A230 and Q293 in the STING protein. These residues may play a critical role in modulating the cell death pathway without affecting the canonical STING signaling pathways. The unique structural configuration or functional properties of these residues could be responsible for the differential effects on CD4 T cell death. Dimerization dynamics: STING functions as a homodimer, and the HAQ and AQ alleles may alter the dimerization dynamics of the STING protein. By influencing the formation of STING dimers, these alleles could impact the downstream signaling pathways that lead to CD4 T cell death while preserving the canonical STING signaling functions. Cell type-specific responses: The HAQ and AQ alleles may exhibit cell type-specific effects, particularly in CD4 T cells, that result in the prevention of cell death. These alleles could modulate the intracellular signaling cascades in a manner that protects CD4 T cells from STING-induced death while allowing for the activation of other STING-mediated pathways in the cell. Regulatory protein interactions: The HAQ and AQ alleles may interact with specific regulatory proteins or signaling molecules in CD4 T cells that regulate the cell death pathway. By influencing these interactions, the alleles could create a protective effect against STING-induced cell death while maintaining the integrity of other STING signaling pathways.

Could targeting the STING-CD4 T cell death axis be a viable therapeutic strategy for inflammatory diseases, and how might this be influenced by the patient's underlying TMEM173 genotype?

Targeting the STING-CD4 T cell death axis could indeed be a promising therapeutic strategy for inflammatory diseases characterized by CD4 T cell depletion. By modulating the STING pathway to prevent excessive CD4 T cell death, it may be possible to restore immune homeostasis and reduce inflammation in conditions such as autoimmune diseases, viral infections, and inflammatory disorders. The patient's underlying TMEM173 genotype, particularly the presence of HAQ or AQ alleles, could significantly influence the efficacy and safety of targeting the STING-CD4 T cell death axis. Individuals with HAQ or AQ alleles, which have been shown to prevent STING-induced CD4 T cell death, may respond differently to therapies that modulate the STING pathway compared to those with other TMEM173 genotypes. For patients with HAQ or AQ alleles, therapies that target the STING-CD4 T cell death axis may need to be tailored to avoid interfering with the protective mechanisms conferred by these alleles. On the other hand, individuals with other TMEM173 genotypes may benefit from interventions that specifically target STING-induced CD4 T cell death to restore immune function and mitigate inflammation. Understanding the patient's TMEM173 genotype could help personalize treatment approaches and optimize therapeutic outcomes in inflammatory diseases where STING-mediated CD4 T cell death plays a significant role.