Sex Differences in Immune Responses

Main Article Content

Ziyi Lu
School of Stomatology, Chongqing Medical University, Chongqing, China

DOI: https://doi.org/10.70267/emsgh.v3.4857

Keywords

sex hormones, X-chromosome inactivation, adaptive immune cells, innate immune cells

Abstract

Biological sex has a significant impact on the immune system and immune-related diseases. Females exhibit a stronger immune response and are therefore more vulnerable to multiple autoimmune diseases. Males are comparatively more susceptible to specific viral, bacterial, parasitic, and fungal infections. Although sex hormones contribute to sexual differences in immune cell population composition and functions, the presence of two X chromosomes in females suggests that differential expression of a large number of X-linked immune-related genes, accompanied by abnormalities in X-chromosome inactivation, may also contribute to the sex-biased functions of innate and adaptive immune cells in health and disease. A comprehensive and multi-perspective understanding of this sex difference would have vital importance for planning and implementing personalized and precision immunotherapies.

Abstract 14 | PDF Downloads 8

References

  • [1] Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nature Reviews Immunology, 16(10), 626–638. https://doi.org/10.1038/nri.2016.90
  • [2] Silva, J., & Iwasaki, A. (2024). Sex differences in postacute infection syndromes. Science Translational Medicine, 16(773), Article eado2102. https://doi.org/10.1126/scitranslmed.ado2102
  • [3] Forsyth, K. S., Jiwrajka, N., Lovell, C. D., Toothacre, N. E., & Anguera, M. C. (2024). The conneXion between sex and immune responses. Nature Reviews Immunology, 24(7), 487–502. https://doi.org/10.1038/s41577-024-00996-9
  • [4] Sharma, S., Gibbons, A., & Saphire, E. O. (2025). Sex differences in tissue-specific immunity and immunology. Science, 389(6760), 599–603. https://doi.org/10.1126/science.adx4381
  • [5] Clave, E., Araujo, I. L., Alanio, C., Patin, E., Bergstedt, J., Urrutia, A., Lopez-Lastra, S., Li, Y., Charbit, B., MacPherson, C. R., Hasan, M., Melo-Lima, B. L., Douay, C., Saut, N., Germain, M., Trégouët, D. A., Morange, P. E., Fontes, M., Duffy, D., ... Milieu Intérieur Consortium (2018). Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus. Science Translational Medicine, 10(457), Article eaao2966. https://doi.org/10.1126/scitranslmed.aao2966
  • [6] Patin, E., Hasan, M., Bergstedt, J., Rouilly, V., Libri, V., Urrutia, A., Alanio, C., Scepanovic, P., Hammer, C., Jönsson, F., Beitz, B., Quach, H., Lim, Y. W., Hunkapiller, J., Zepeda, M., Green, C., Piasecka, B., Leloup, C., Rogge, L., ... Albert, M. L. (2018). Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. Nature Immunology, 19(3), 302–314. https://doi.org/10.1038/s41590-018-0049-7
  • [7] Bongen, E., Lucian, H., Khatri, A., Fragiadakis, G. K., Bjornson, Z. B., Nolan, G. P., Utz, P. J., & Khatri, P. (2019). Sex differences in the blood transcriptome identify robust changes in immune cell proportions with aging and influenza infection. Cell Reports, 29(7), 1961–1973.e4. https://doi.org/10.1016/j.celrep.2019.10.019
  • [8] Amadori, A., Zamarchi, R., De Silvestro, G., Forza, G., Cavatton, G., Danieli, G. A., Clementi, M., & Chieco-Bianchi, L. (1995). Genetic control of the CD4/CD8 T-cell ratio in humans. Nature Medicine, 1(12), 1279–1283. https://doi.org/10.1038/nm1295-1279
  • [9] Dodd, K. C., & Menon, M. (2022). Sex bias in lymphocytes: Implications for autoimmune diseases. Frontiers in Immunology, 13, Article 945762. https://doi.org/10.3389/fimmu.2022.945762
  • [10] Abdullah, M., Chai, P.-S., Chong, M.-Y., Tohit, E. R. M., Ramasamy, R., Pei, C. P., & Vidyadaran, S. (2012). Gender effect on in vitro lymphocyte subset levels of healthy individuals. Cellular Immunology, 272(2), 214–219. https://doi.org/10.1016/j.cellimm.2011.10.009
  • [11] Reina-Campos, M., Monell, A., Ferry, A., Luna, V., Cheung, K. P., Galletti, G., Scharping, N. E., Takehara, K. K., Quon, S., Challita, P. P., Boland, B., Lin, Y. H., Wong, W. H., Indralingam, C. S., Neadeau, H., Alarcón, S., Yeo, G. W., Chang, J. T., Heeg, M., & Goldrath, A. W. (2025). Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted. Nature, 639(8054), 483–492. https://doi.org/10.1038/s41586-024-08466-x
  • [12] Melzer, S., Zachariae, S., Bocsi, J., Engel, C., Löffler, M., & Tárnok, A. (2015). Reference intervals for leukocyte subsets in adults: Results from a population-based study using 10-color flow cytometry. Cytometry Part B: Clinical Cytometry, 88(4), 270–281. https://doi.org/10.1002/cyto.b.21234
  • [13] Huang, Z., Chen, B., Liu, X., Li, H., Xie, L., Gao, Y., Duan, R., Li, Z., Zhang, J., Zheng, Y., & Su, W. (2021). Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proceedings of the National Academy of Sciences, 118(33), Article e2023216118. https://doi.org/10.1073/pnas.2023216118
  • [14] Wikby, A., Månsson, I. A., Johansson, B., Strindhall, J., & Nilsson, S. E. (2008). The immune risk profile is associated with age and gender: Findings from three Swedish population studies of individuals 20–100 years of age. Biogerontology, 9(5), 299–308. https://doi.org/10.1007/s10522-008-9138-6
  • [15] Peckham, H., Radziszewska, A., Sikora, J., de Gruijter, N. M., Restuadi, R., Kartawinata, M., Martin-Gutierrez, L., Robinson, G. A., Deakin, C. T., Wedderburn, L. R., Jury, E. C., Butler, G., Chambers, E. S., Rosser, E. C., & Ciurtin, C. (2025). Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes. Journal of Experimental Medicine, 222(4), Article e20241253. https://doi.org/10.1084/jem.20241253
  • [16] Khan, S. R., van der Burgh, A. C., Peeters, R. P., van Hagen, P. M., Dalm, V. A. S. H., & Chaker, L. (2021). Determinants of serum immunoglobulin levels: A systematic review and meta-analysis. Frontiers in Immunology, 12, Article 664526. https://doi.org/10.3389/fimmu.2021.664526
  • [17] Carr, E. J., Dooley, J., Garcia-Perez, J. E., Lagou, V., Lee, J. C., Wouters, C., Meyts, I., Goris, A., Boeckxstaens, G., Linterman, M. A., & Liston, A. (2016). The cellular composition of the human immune system is shaped by age and cohabitation. Nature Immunology, 17(4), 461–468. https://doi.org/10.1038/ni.3371
  • [18] Bain, B. J., & England, J. M. (1975). Normal haematological values: Sex difference in neutrophil count. BMJ, 1(5953), 306–309. https://doi.org/10.1136/bmj.1.5953.306
  • [19] Molloy, E. J., O'Neill, A. J., Grantham, J. J., Sheridan-Pereira, M., Fitzpatrick, J. M., Webb, D. W., & Watson, R. W. G. (2003). Sex-specific alterations in neutrophil apoptosis: The role of estradiol and progesterone. Blood, 102(7), 2653–2659. https://doi.org/10.1182/blood-2003-02-0649
  • [20] Heimbeck, I., Hofer, T. P. J., Eder, C., Wright, A. K., Frankenberger, M., Marei, A., Boghdadi, G., Scherberich, J., & Ziegler‐Heitbrock, L. (2010). Standardized single-platform assay for human monocyte subpopulations: Lower CD14+CD16++ monocytes in females. Cytometry Part A, 77A(9), 823–830. https://doi.org/10.1002/cyto.a.20942
  • [21] Cheng, M. I., Li, J. H., Riggan, L., Chen, B., Tafti, R. Y., Chin, S., Ma, F., Pellegrini, M., Hrncir, H., Arnold, A. P., O'Sullivan, T. E., & Su, M. A. (2023). The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature Immunology, 24(5), 780–791. https://doi.org/10.1038/s41590-023-01463-8
  • [22] Schmiedel, B. J., Singh, D., Madrigal, A., Valdovino-Gonzalez, A. G., White, B. M., Zapardiel-Gonzalo, J., Ha, B., Altay, G., Greenbaum, J. A., McVicker, G., Seumois, G., Rao, A., Kronenberg, M., Peters, B., & Vijayanand, P. (2018). Impact of genetic polymorphisms on human immune cell gene expression. Cell, 175(6), 1701–1715.e16. https://doi.org/10.1016/j.cell.2018.10.022
  • [23] Lee, J., Nicosia, M., Hong, E. S., Silver, D. J., Li, C., Bayik, D., Watson, D. C., Lauko, A., Kay, K. E., Wang, S. Z., Johnson, S., McGraw, M., Grabowski, M. M., Kish, D. D., Desai, A. B., Goodman, W. A., Cameron, S. J., Okada, H., Valujskikh, A., ... Lathia, J. D. (2023). Sex-biased T-cell exhaustion drives differential immune responses in glioblastoma. Cancer Discovery, 13(9), 2090–2105. https://doi.org/10.1158/2159-8290.cd-22-0869
  • [24] Conforti, F., Pala, L., Di Mitri, D., Catania, C., Cocorocchio, E., Laszlo, D., Ceresoli, G., Locatelli, M., Facella, F., De Pas, T., Rambaldi, B., Rambaldi, A., Viale, G., Bagnardi, V., Giaccone, G., & Mantovani, A. (2025). Sex hormones, the anticancer immune response, and therapeutic opportunities. Cancer Cell, 43(3), 343–360. https://doi.org/10.1016/j.ccell.2025.02.013
  • [25] Hoffmann, J. P., Liu, J. A., Seddu, K., & Klein, S. L. (2023). Sex hormone signaling and regulation of immune function. Immunity, 56(11), 2472–2491. https://doi.org/10.1016/j.immuni.2023.10.008
  • [26] Davis, K. E., Neinast, M. D., Sun, K., Skiles, W. M., Bills, J. D., Zehr, J. A., Zeve, D., Hahner, L. D., Cox, D. W., Gent, L. M., Xu, Y., Wang, Z. V., Khan, S. A., & Clegg, D. J. (2013). The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Molecular Metabolism, 2(3), 227–242. https://doi.org/10.1016/j.molmet.2013.05.006
  • [27] Stranahan, A. M., Guo, D.-H., Yamamoto, M., Hernandez, C. M., Khodadadi, H., Baban, B., Zhi, W., Lei, Y., Lu, X., Ding, K., & Isales, C. M. (2023). Sex differences in adipose tissue distribution determine susceptibility to neuroinflammation in mice with dietary obesity. Diabetes, 72(2), 245–260. https://doi.org/10.2337/db22-0192
  • [28] Chi, L., Liu, C., Gribonika, I., Gschwend, J., Corral, D., Han, S. J., Lim, A. I., Rivera, C. A., Link, V. M., Wells, A. C., Bouladoux, N., Collins, N., Lima-Junior, D. S., Enamorado, M., Rehermann, B., Laffont, S., Guéry, J. C., Tussiwand, R., Schneider, C., & Belkaid, Y. (2024). Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis. Science, 384(6692), Article eadk6200. https://doi.org/10.1126/science.adk6200
  • [29] Robert, J. (2023). Sex differences in vascular endothelial cells. Atherosclerosis, 384, Article 117278. https://doi.org/10.1016/j.atherosclerosis.2023.117278
  • [30] Miquel, C.-H., Faz-Lopez, B., & Guéry, J.-C. (2023). Influence of X chromosome in sex-biased autoimmune diseases. Journal of Autoimmunity, 137, Article 102992. https://doi.org/10.1016/j.jaut.2023.102992
  • [31] Tukiainen, T., Villani, A.-C., Yen, A., Rivas, M. A., Marshall, J. L., Satija, R., Aguirre, M., Gauthier, L., Fleharty, M., Kirby, A., Cummings, B. B., Castel, S. E., Karczewski, K. J., Aguet, F., Byrnes, A., GTEx Consortium, Lappalainen, T., Regev, A., Ardlie, K. G., ... MacArthur, D. G. (2017). Landscape of X chromosome inactivation across human tissues. Nature, 550(7675), 244–248. https://doi.org/10.1038/nature24265
  • [32] Berletch, J. B., Ma, W., Yang, F., Shendure, J., Noble, W. S., Disteche, C. M., & Deng, X. (2015). Escape from X inactivation varies in mouse tissues. PLOS Genetics, 11(3), Article e1005079. https://doi.org/10.1371/journal.pgen.1005079
  • [33] Marahrens, Y., Panning, B., Dausman, J., Strauss, W., & Jaenisch, R. (1997). Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes & Development, 11(2), 156–166. https://doi.org/10.1101/gad.11.2.156
  • [34] Anguera, M. C., Sadreyev, R., Zhang, Z., Szanto, A., Payer, B., Sheridan, S. D., Kwok, S., Haggarty, S. J., Sur, M., Alvarez, J., Gimelbrant, A., Mitalipova, M., Kirby, J. E., & Lee, J. T. (2012). Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell, 11(1), 75–90. https://doi.org/10.1016/j.stem.2012.03.008
  • [35] Adrianse, R. L., Smith, K., Gatbonton-Schwager, T., Sripathy, S. P., Lao, U., Foss, E. J., Boers, R. G., Boers, J. B., Gribnau, J., & Bedalov, A. (2018). Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion. Epigenetics & Chromatin, 11(1), Article 50. https://doi.org/10.1186/s13072-018-0219-8
  • [36] Yang, L., Yildirim, E., Kirby, J. E., Press, W., & Lee, J. T. (2020). Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut. Proceedings of the National Academy of Sciences, 117(8), 4262–4272. https://doi.org/10.1073/pnas.1917203117
  • [37] Yildirim, E., Kirby, J. E., Brown, D. E., Mercier, F. E., Sadreyev, R. I., Scadden, D. T., & Lee, J. T. (2013). Xist RNA is a potent suppressor of hematologic cancer in mice. Cell, 152(4), 727–742. https://doi.org/10.1016/j.cell.2013.01.034
  • [38] Boggs, B. A., Cheung, P., Heard, E., Spector, D. L., Chinault, A. C., & Allis, C. D. (2002). Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nature Genetics, 30(1), 73–76. https://doi.org/10.1038/ng787
  • [39] Plath, K., Fang, J., Mlynarczyk-Evans, S. K., Cao, R., Worringer, K. A., Wang, H., de la Cruz, C. C., Otte, A. P., Panning, B., & Zhang, Y. (2003). Role of histone H3 lysine 27 methylation in X inactivation. Science, 300(5616), 131–135. https://doi.org/10.1126/science.1084274
  • [40] Costanzi, C., Stein, P., Worrad, D. M., Schultz, R. M., & Pehrson, J. R. (2000). Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos. Development, 127(11), 2283–2289. https://doi.org/10.1242/dev.127.11.2283
  • [41] Clemson, C. M., McNeil, J. A., Willard, H. F., & Lawrence, J. B. (1996). XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear/chromosome structure. Journal of Cell Biology, 132(3), 259–275. https://doi.org/10.1083/jcb.132.3.259
  • [42] Wang, J., Syrett, C. M., Kramer, M. C., Basu, A., Atchison, M. L., & Anguera, M. C. (2016). Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proceedings of the National Academy of Sciences, 113(14), E2029–E2038. https://doi.org/10.1073/pnas.1520113113
  • [43] Syrett, C. M., Sindhava, V., Hodawadekar, S., Myles, A., Liang, G., Zhang, Y., Nandi, S., Cancro, M., Atchison, M., & Anguera, M. C. (2017). Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells. PLOS Genetics, 13(10), Article e1007050. https://doi.org/10.1371/journal.pgen.1007050
  • [44] Syrett, C. M., Paneru, B., Sandoval-Heglund, D., Wang, J., Banerjee, S., Sindhava, V., Behrens, E. M., Atchison, M., & Anguera, M. C. (2019). Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. JCI Insight, 4(7), Article e126751. https://doi.org/10.1172/jci.insight.126751
  • [45] Syrett, C. M., Sindhava, V., Sierra, I., Dubin, A. H., Atchison, M., & Anguera, M. C. (2018). Diversity of epigenetic features of the inactive X-chromosome in NK cells, dendritic cells, and macrophages. Frontiers in Immunology, 9, Article 3087. https://doi.org/10.3389/fimmu.2018.03087
  • [46] Pyfrom, S., Paneru, B., Knox, J. J., Cancro, M. P., Posso, S., Buckner, J. H., & Anguera, M. C. (2021). The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients. Proceedings of the National Academy of Sciences, 118(24), Article e2024624118. https://doi.org/10.1073/pnas.2024624118

Article Sidebar

Full Text
PDF
Information
Copy Publication Information
Published
Oct 29, 2026
Issue
Vol. 3 (2026)
Section
Articles
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite

Sex Differences in Immune Responses. (2026). Explore Medical Science and Global Health, 3, 48-57. https://doi.org/10.70267/emsgh.v3.4857