TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells
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Abstract
Background: Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. Method: In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14 + monocytes and CD4 + T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. Results: Using RNA FISH, we show that TLR8 , like TLR7 , evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. Conclusions: TLR8 , mirroring TLR7 , escapes XCI in human monocytes and CD4 + T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.
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The contrasting roles of AmtRNA in males and females may be linked to the presence of TLR-7 and -8 genes on the X chromosome and their potential to escape X chromosome inactivation, thus leaving females with more gene copies of these TLRs.
“How exactly AmtRNA may play contrasting roles in males and females is unclear, but this may be linked to the presence of TLR-7 and -8 genes on the X chromosome and their potential to escape X chromosome inactivation, thus leaving females with more gene copies of these TLRs [31,32].”
From Antimitochondrial antibodies in systemic lupus erythematosus are associated with and predict nephritis, arterial vascular events, and mortality (2026) · cites this paper as [32]
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Altered X-chromosome inactivation predisposes to autoimmunity
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Self-citationSex-Based Differences in Asthma: Pathophysiology, Hormonal Influence, and Genetic Mechanisms
Borrelli, R., Brussino, L., Sardo, L. L., Quinternetto, A., Vitali, I., Bagnasco, D., Boem, M., Corradi, F., Badiu, I., Negrini, S. M., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115288 · Cited by 38 · see citing works
RETRACTED: Comprehensive review for non-coding RNAs: From mechanisms to therapeutic applications
Zhang, Y., Zhan, L., Jiang, X., & Tang, X. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116218 · Cited by 33 · see citing works
RetractedUnderstanding Sex Differences in Autoimmune Diseases: Immunologic Mechanisms
Kim, Y., Jung, Y., Kang, I., & Yeo, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157101 · Cited by 32 · see citing works
Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus
von Hofsten, S., Fenton, K. A., & Pedersen, H. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105351 · Cited by 30 · see citing works
Aging promotes reactivation of the Barr body at distal chromosome regions
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Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity
Kioon, M. D. A., Laurent, P., Chaudhary, V., Du, Y., Crow, M. K., & Barrat, F. J. (2024) · Immunological Reviews · doi:10.1111/imr.13331 · Cited by 28 · see citing works
Self-citationDu, Y., Faz-López, B., Kioon, M. D. A., Cénac, C., Pierides, M., Lakin, K. S., Spiera, R., Chaumeil, J., Truchetet, M., Gordon, J., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231809 · Cited by 28 · see citing works
Self-citationSmall RNA and Toll-like receptor interactions: origins and disease mechanisms
Yu, J., Zhang, X., Cai, C., Zhou, T., & Chen, Q. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.01.004 · Cited by 25 · see citing works
Identifying genetic errors of immunity due to mosaicism
Schmitz, E. G., Griffith, M., Griffith, O. L., & Cooper, M. A. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20241045 · Cited by 17 · see citing works
Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame?
Vieira, A. A., Almada-Correia, I., Inácio, J., Costa‐Reis, P., & da Rocha, S. T. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00650-y · Cited by 16 · see citing works
Sexual dimorphism in immunity and longevity among the oldest old
Arakelyan, N. A., Kupriyanova, D. A., Vasiļevska, J., & Rogaev, E. I. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1525948 · Cited by 14 · see citing works
The X Factor in Immunity: Sex Differences Shaped by the X Chromosome
Radovanovic, K., Wynalda, M., & Anguera, M. C. (2026) · Immunological Reviews · doi:10.1111/imr.70107 · Cited by 13 · see citing works
Sex Bias in Systemic Sclerosis: from Clinical to Immunological Differences
Sakkas, L. I., Bogdanos, D. P., & Chikanza, I. C. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09062-1 · Cited by 12 · see citing works
Tampé, J., Monni, E., Palma-Tortosa, S., Brogårdh, E., Böiers, C., Lindgren, A. G., & Kokaia, Z. (2024) · PLoS ONE · doi:10.1371/journal.pone.0300946 · Cited by 9 · see citing works
Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains
Saidoune, F., Lee, D., Domizio, J. D., Floc’h, C. L., Jenelten, R., Pen, J. L., Bondet, V., Joncic, A., Morren, M., Béziat, V., et al. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20231467 · Cited by 9 · see citing works
Zou, J., Xiao, Y., Zhang, L., Zuo, Z., Wang, X., Liao, X., Cui, N., Jin, J., Qian, Z., Wu, A., et al. (2025) · Critical Care · doi:10.1186/s13054-025-05616-z · Cited by 9 · see citing works
The Inactive X Chromosome: A Genetic Driver of Female‐Biased Rheumatic Autoimmune Disorders?
Ferrayé, L., Nieucel, M., Savignac, M., Chaumeil, J., & Guéry, J. (2025) · European Journal of Immunology · doi:10.1002/eji.202451331 · Cited by 10 · see citing works
Self-citationSex as a modifier of genetic risk for type 1 diabetes
Qu, H., & Hakonarson, H. H. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70124 · Cited by 8 · see citing works
Miles, M. A., Huttmann, T. D., Liong, S., Liong, F., O’Leary, J. J., Brooks, D. A., & Selemidis, S. (2025) · Viruses · doi:10.3390/v17030428 · Cited by 7 · see citing works
Xu, X., Yu, R., Yang, Z., Li, C., Xiong, H., & Li, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1605185 · Cited by 8 · see citing works
Arnold, D. E., Kaviany, S., Aluri, J., Calvo, K. R., Mehta, S. S., Tobin, J. M., Schuettpelz, L. G., Saucier, N., Schmitz, E. G., Murguía-Favela, L. E., et al. (2025) · Blood Advances · doi:10.1182/bloodadvances.2025016338 · Cited by 7 · see citing works
Bulut, O. P., Temba, G. S., Koeken, V. A. C. M., Moorlag, S. J. C. F. M., de Bree, L. C. J., Mourits, V. P., Kullaya, V. I., Jaeger, M., Qi, C., Riksen, N. P., et al. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111916 · Cited by 7 · see citing works
Sex Differences in Metabolite–Immune Circuits of Neuroinflammation
Saminathan, P., Corey, M., Gibbons, A., Rayadurgam, M., Reddy, N., Ramesh, P., & Sharma, S. (2026) · Immunological Reviews · doi:10.1111/imr.70114 · Cited by 8 · see citing works
Asthma endotypes and theratypes
Agache, I. O., Li, S., Zheng, Y., & Gao, Y. (2026) · Chinese Medical Journal - Pulmonary and Critical Care Medicine · doi:10.1016/j.pccm.2026.02.006 · Cited by 5 · see citing works
Barrat, F. J., & Guéry, J. (2025) · Immunological Reviews · doi:10.1111/imr.70074 · Cited by 4 · see citing works
Self-citationKumar, V. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl27118 · Cited by 4 · see citing works
Ventura, M. T., Giuliano, A. F. M., Boni, E., Brussino, L., Buquicchio, R., Conte, M., Costantino, M. T., Crivellaro, M., Giuliani, I. M. R., Losa, F., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199605 · Cited by 3 · see citing works
Extracellular microRNAs modulate human microglial function through TLR8
Weidling, H., Motta, E., Kuhrt, L. D., Krüger, C., Figueiredo, C. A., Wallach, T., Frahm, S., Diecke, S., Wolf, S. A., Kettenmann, H., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1645062 · Cited by 3 · see citing works
Holbrook, B. C., Clemens, E. A., & Alexander‐Miller, M. A. (2024) · Vaccines · doi:10.3390/vaccines12040415 · Cited by 3 · see citing works
UBA1-CDK16 : A Sex-Specific Chimeric RNA and Its Role in Immune Sexual DimorphismPreprint
Shi, X., Facemire, L., Singh, S., Kumar, S., Cornelison, R., Liang, C., Qin, F., Liu, A., Lin, S., Tang, Y., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.13.580120 · Cited by 3 · see citing works
Becker, Y. L. C., Boilard, É., Rollet-Labelle, E., Lood, C., Julien, A.-S., Abrahamowicz, M., Allaeys, I., Choi, M., Leclerc, J., Lévesque, T., et al. (2026) · Annals of the Rheumatic Diseases · doi:10.1016/j.ard.2025.11.007 · Cited by 3 · see citing works
Cihan, H., Güngör, Ö., Kocabaş, G. Ü., Koroglu, E. P., Gülpınar, K., Parıltay, E., Ardeniz, Ö., T'Sjoen, G. G., Leffler, J., Winzeler, B. F., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1752956 · Cited by 2 · see citing works
Sexual Dimorphism in Allergic and Mast Cell-Associated Diseases
Kotha, A., Maldonado, T. D., Hamze, H., Hussain, Z. Y., Gobinathan, N., Yao, A. Z., Abudulkadir, M., Ching, J. M., & Ryan, J. J. (2026) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-026-09150-w · Cited by 2 · see citing works
Régulation du chromosome X et spécificités fonctionnelles des cellules femelles
Chaumeil, J., & Morey, C. (2024) · médecine/sciences · doi:10.1051/medsci/2024179 · Cited by 3 · see citing works
Self-citationGomes, F. D. C., Galhardo, D. D. R., Navegante, A. C. G., dos Santos, G. S., Dias, H. A. A. L., Júnior, J. R. L. D., Pierre, M. E., Luz, M. O., & Neto, J. S. D. M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0305760 · Cited by 2 · see citing works
Bustos-Merlo, A., Navarrete‐Navarrete, N., Navarrete, L. G., & Martı́n-Armada, M. (2024) · Frontiers in Lupus · doi:10.3389/flupu.2024.1334214 · Cited by 1 · see citing works
Jurczuk, A., Bałdyga, P., Płoński, A., Jurczuk, M., & Garley, M. (2025) · Cells · doi:10.3390/cells14231902 · Cited by 1 · see citing works
The impact of X chromosome inactivation on human health
Gu, J., & Chen, Q. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1845863 · Cited by 1 · see citing works
Shi, X., Blackburn, L. L., Singh, S., Glowczyk-Gluc, M., Tajammal, A., Zahra, S., Kumar, S., Cornelison, R., Liang, C., Qin, F., et al. (2026) · Science Advances · doi:10.1126/sciadv.adz9784 · Cited by 1 · see citing works
Mosaic TLR8 gain-of-function in an elderly female treated with JAK inhibitor and adjunctive therapy
Patel, J. A., Saucier, N., Gil, H. M., Schmitz, E. G., Ruzinova, M. B., Saffaf, A., Blinder, M. A., Mehta–Shah, N., Crees, Z. D., Cooper, M. A., et al. (2026) · Journal of Human Immunity · doi:10.70962/jhi.20260113 · Cited by 1 · see citing works
McGuire, G. R., Klimas, A. S., Deegan, D. F., Calendo, G., Alapatt, C. F., Zaidi, M. R., Bottaro, A., & Engel, N. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.16.706181 · Cited by 1 · see citing works
Revanna, J. S., Wessendorf-Rodriguez, K. A., Xiao, Q., Sabedot, T. S., Cuoco, M. S., Sarkar, S., Zhou-Yang, L., Lim, C. K., Prozapas, V. N., Wooldridge, R., et al. (2026) · SSRN Electronic Journal · doi:10.64898/2026.05.12.724612 · Cited by 2 · see citing works
Mahla, R. S. (2024) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.15033
Genetic biomarker prediction based on gender disparity in asthma throughout machine learning
Chen, C., Yuan, F., Meng, X., Peng, F., Shao, X., Wang, C., Shen, Y., Du, H., Lv, D., Zhang, N., et al. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1397746
The Effects of Biological Sex on Cellular Immunity
Álvarez‐Sánchez, N., & Dunn, S. E. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00189-7
Faz-López, B., Allart, S., Chaumeil, J., & Guéry, J. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4997-8_13
Self-citationNotohardjo, J. C. L., Toffoli, E. C., Muijlwijk, T., van den Hout, M. F. C. M., Kandiah, V., Labots, M., van de Ven, R., van den Eertwegh, A. J. M., & de Gruijl, T. D. (2026) · OncoImmunology · doi:10.1080/2162402x.2026.2662708
Sex-Related Differences in Circular RNA Expression in Multiple Sclerosis: A Pilot Study
Lodde, V., Zarbo, I. R., Farina, G., Zoroddu, E., Solla, P., Delogu, G., Gorospe, M., Floris, M., Campesi, I., & Idda, M. L. (2026) · Journal of Molecular Neuroscience · doi:10.1007/s12031-026-02548-3
Reyes-Noriega, N., Leija-Martínez, J. J., Sánchez‐Muñoz, F., Hernández-Díazcouder, A., Tavera-Alonso, C., Villafaña, S., Díaz, D. J. M. M., Del-Rio-Navarro, B. E., & Huang, F. (2026) · Nutrients · doi:10.3390/nu18121885
Jefferies, C. A., Bose, M., & Kumar, A. N. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-33957-8.00017-2
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A Sex-Specific Chimeric RNA in Female Immune Regulation: Case Study
Shi, X., Blackburn, L. L., Singh, S., Glowczyk-Gluc, M., Zahra, S., Wu, P., & Li, H. (2026) · Methods in molecular biology · doi:10.1007/978-1-0716-5202-2_17
Sex-dependent mechanisms in rheumatic diseases
Volkmann, E. R., Herzog, E. L., & Feghali‐Bostwick, C. A. (2026) · Nature Reviews Rheumatology · doi:10.1038/s41584-026-01405-2
Endogenous DNA Homeostasis, Genome Instability and cGAS-STING Activation in Autoimmune Disease
Waseem, M., Imtiaz, A., Datta, A., & Contreras-Galindo, R. (2026) · IntechOpen eBooks · doi:10.5772/intechopen.1017776
Sex-specific differences in ADAR editing patterns in response to SARS-CoV-2 infectionsPreprint
Nair, A. M., & Piontkivska, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.29.755432
Cardiovascular phenotypes in women with Sjögren disease: hormonal, immune, and clinical perspectives
Coppi, F., Angeli, F., Bucciarelli, V., Moscucci, F., Crisci, G., Renda, G., Nodari, S., Pagnoni, G., Bauce, B., Montisci, R., et al. (2026) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2026.103481
TLR8 gain-of-function syndrome
Gil, H. M., & Cooper, M. A. (2026) · Journal of Human Immunity · doi:10.70962/jhi.20260172
- Authors
- Youness, A., Cenac, C., Faz-López, B., Grunenwald, S., Barrat, F. J., Chaumeil, J., Mejía, J. E., & Guéry, J.-C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Toulouse (FR)
- Hospital for Special Surgery (US)
- Corresponding author
- Mejía, José Enrique
- Guéry, Jean-Charles
- ORCID
- Venue
- Biology of Sex Differences
- Published
- 2023-09-18
- Volume
- 14
- Issue
- 1
- Pages
- 60-60
- ISSN
- 2042-6410 (ISSN-L)
- PMC
- PMC10506212
- OpenAlex
- W4386839549
- Cited by
- 58
- References
- 81
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 15
- FWCI
- 9.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Biology of Sex Differences (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-20-CE15-0014, ANR-20-COV8-0004-01)
- Sidaction
- Fonds de dotation CSL Behring pour la recherche
- Foundation for Research in Rheumatology
- Région Occitanie/Pyrénées-Méditerranée
- Scleroderma Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TLR8, X chromosome inactivation, TLR7, monocytes, CD4+ T cells, Klinefelter syndrome, X-linked genes, sex differences, RNA fluorescence in situ hybridization, XIST, innate immunity, autoimmune disease susceptibility
- MeSH terms
- Female, Humans, Male, Monocytes, T-Lymphocytes, CD4-Positive T-Lymphocytes, In Situ Hybridization, Fluorescence, X Chromosome Inactivation, Toll-Like Receptor 7, Toll-Like Receptor 8
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