TMEM173 encodes MPYS/STING, is an innate immune sensor for cyclic dinucleotides (CDNs) playing a critical role in infection, inflammation, and cancer. The R71H-G230A-R293Q (HAQ) of TMEM173 is the second most common human TMEM173 allele. Here, using data from 1000Genome Project, we found that homozygous HAQ individuals account for ~16.1% of East Asians and ~2.8% of Europeans while Africans have no homozygous HAQ individuals. Using B cells from homozygous HAQ carriers, we found, surprisingly, that HAQ/HAQ carriers express extremely low MPYS protein and have decreased TMEM173 transcript. Consequently, the HAQ/HAQ B cells do not respond to CDNs. We subsequently generated an HAQ knock-in mouse expressing mouse-equivalent of the HAQ allele (mHAQ). The mHAQ mouse has decreased MPYS protein in B cells, T cells, Ly6Chi monocytes, bone-marrow-derived DC and lung tissue. The mHAQ mouse also does not respond to CDNs in vitro and in vivo. Lastly, Pneumovax®23 whose efficacy depends on TMEM173, is less effective in the mHAQ mice than the WT mice. We conclude that HAQ is a null TMEM173 allele. Our findings have a significant impact on research related to MPYS-mediated human diseases and medicine.

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8 T-cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cell (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that DCs resident in lung tumor tissues or DCs exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL12 and IFNI. Tumor-conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking critical for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I IFN downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DCs conditioned by lactate failed to prime antitumor responses These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches. These findings provide insight into the cell-intrinsic and cell-extrinsic mechanisms that cause loss of presentation of tumor-specific antigens in lung cancer tissues. .

The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires’ disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires’ disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection.Trial registrationClinicalTrials.gov DRKS00005274, German Clinical Trials Register