Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 2, Pages 776-787Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1601585
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Funding
- National Institute of Allergy and Infectious Diseases [1R56AI110606, 1R01AI110606, R21AI099346, 1R21AI125999]
- Gary and Janis Grover Young Scientist Award
- Deutsche Forschungsgemeinschaft (DFG) [OP 86/10-1]
- Sonderforschungsbereich Grant [SFB-TR84]
- DFG [GRK1673]
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TMEM173 encodes MPYS/STING and 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. In this study, using data from the 1000 Genomes Project we found that homozygous HAQ individuals account for similar to 16.1% of East Asians and similar to 2.8% of Europeans whereas 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 a decreased TMEM173 transcript. Consequently, the HAQ/HAQ B cells do not respond to CDNs. We subsequently generated an HAQ knock-in mouse expressing a mouse equivalent of the HAQ allele (mHAQ). The mHAQ mouse has decreased MPYS protein in B cells, T cells, Ly6C(hi) monocytes, bone marrow-derived dendritic cells, and lung tissue. The mHAQ mouse also does not respond to CDNs in vitro and in vivo. Lastly, Pneumovax 23, with an efficacy that depends on TMEM173, is less effective in mHAQ mice than in wild type 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.
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