Hai-Hui Xue, MD, PhD

Professor of Microbiology and Immunology

Contact Information

Primary Office
3-772 Bowen Science Building
51 Newton Rd
Iowa City, IA 52242

3-701 Bowen Science Building
51 Newton Rd
Iowa City, IA 52242


MD, Medicine, China Medical University
MS, Biochemistry, China Medical University
PhD, Biochemistry, Hamamatsu University School of Medicine
Postdoctoral Fellow, Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health

Education/Training Program Affiliations

Biomedical Science Program, Department of Microbiology Graduate Program, Interdisciplinary Graduate Program in Immunology, Medical Scientist Training Program

Center, Program and Institute Affiliations

Center for Immunology and Immune-based Diseases, Holden Comprehensive Cancer Center

Research Summary

The identity of a cell type is determined by genes it expresses and those it silences, where transcriptional and epigenetic regulations play a central role. Differentiation of hematopoietic stem cells to antigen responding T cells is accompanied by many stages of cell identity transition. Our lab aims to decode how key transcription factors coopts epigenetic mechanisms to maintain the cell identity and instigate the transitions during the following biological processes:

1. T cell development in the thymus, from immature progenitors, to bipotent cells, and then mature CD8+ and CD4+ single positive cells.

2. CD8+ T cell differentiation in lymphoid organs in response to infection and/or vaccination, including the bifurcation of generating cytotoxic effector CD8+ T cells vs memory precursors, and their further transition into lasting memory CD8+ T cells.

3. CD4+ T cell differentiation in lymphoid organs in response to infection and/or vaccination, including the bifurcation of generating B cell-helping T follicular helper cells vs interferon-producing T helper 1 cells, and their transition to memory CD4+ T cells.

Our current focus is on Tcf1 and Lef1 transcription factors, their co-activator beta-catenin, and corepressor TLE/Groucho proteins. We are using molecular biology, genomics, proteomics, and bioinformatics approaches to decipher their distinct and conserved roles in programming different immunological processes.


Jensen, I. J., Winborn, C. S., Fosdick, M. G., Shao, P., Tremblay, M. M., Shan, Q., Tripathy, S. K., Snyder, C. M., Xue, H., Griffith, T. S., Houtman, J. C. & Badovinac, V. P. (2018). Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections. PLoS Pathog, 14(10), e1007405. PMID: 30379932.

Issuree, P. D., Day, K., Au, C., Raviram, R., Zappile, P., Skok, J. A., Xue, H., Myers, R. M. & Littman, D. R. (2018). Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development. Nat Commun, 9(1), 3594. PMID: 30185805.

Xing, S., Shao, P., Li, F., Zhao, X., Seo, W., Wheat, J. C., Ramasamy, S., Wang, J., Li, X., Peng, W., Yu, S., Liu, C., Taniuchi, I., Sweetser, D. A. & Xue, H. (2018). Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity. J Exp Med, 215(8), 2211-2226. PMID: 30045946.

Xiu, Y., Dong, Q., Li, Q., Li, F., Borcherding, N., Zhang, W., Boyce, B., Xue, H. & Zhao, C. (2018). Stabilization of NF-?B-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. Cell Rep, 22(2), 350-358. PMID: 29320732.

Zhao, D. M., Xue, H. (2018). Tcf1. In S. Choi (Eds.) Encyclopedia of Signaling Molecules, 2nd edition. (2nd edition) Springer.

Gautam, S., Xhu, W., Brohawn, P., Fioravanti, J., Hu, J., Lacey, N., Le Gall, J. B., Hocker, J. D., Telford, W. G., Bhandoola, A., Xue, H., Roychoudhuri, R., Higgs, B., Restifo, N. P., Bender, T. P., Ji, Y. & Gattinoni, L. (In Press). The transcription factor Myb enhances CD8+ T cell stemness and anti-tumor immunity. Nat Immunol.

Li, F., Zeng, Z., Xing, S., Gullicksrud, J. A., Shan, Q., Choi, J., Badovinac, V. P., Crotty, S., Peng, W. & Xue, H. (In Press). Ezh2 programs Tfh differentiation by integrating phosphorylation-dependent activation. Nat Commun.

Danahy, D. B., Anthony, S. M., Jensen, I. J., Hartwig, S. M., Shan, Q., Xue, H., Harty, J. T., Griffith, T. S. & Badovinac, V. P. (2017). Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells. PLoS Pathog, 13(9), e1006569. PMID: 28910403.

Li, F., He, B., Ma, X., Yu, S., Bhave, R. R., Lentz, S. R., Tan, K., Guzman, M. L., Zhao, C. & Xue, H. (2017). Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell, 21(3), 359-373. PMID: 28844837.

Xie, Y., Kaufman, D., Moulton, M. J., Panahi, S., Gaynes, J. A., Watters, H. N., Zhou, D., Xue, H., Fung, C. M., Levine, E. M., Letsou, A., Brennan, K. C. & Dorsky, R. I. (2017). Lef1-dependent hypothalamic neurogenesis inhibits anxiety. PLoS Biol, 15(8), e2002257. PMID: 28837622.

Zhao, D. M., Xue, H. (2017). MLL4 keeps Foxp3 in the loop. Nat Immunol, 18(9), 957-958. PMID: 28829449.

Shan, Q., Zeng, Z., Xing, S., Li, F., Hartwig, S. M., Gullicksrud, J. A., Kurup, S. P., Van Braekel-Budimir, N., Su, Y., Martin, M. D., Varga, S. M., Taniuchi, I., Harty, J. T., Peng, W., Badovinac, V. P. & Xue, H. (2017). The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol, 18(8), 931-939. PMID: 28604718.

Gullicksrud, J. A., Li, F., Xing, S., Zeng, Z., Peng, W., Badovinac, V. P., Harty, J. T. & Xue, H. (2017). Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection. J Immunol, 199(3), 911-919. PMID: 28652395.

Thapa, P., Manso, B., Chung, J. Y., Romera Arocha, S., Xue, H., Angelo, D. B. & Shapiro, V. S. (2017). The differentiation of ROR-?t expressing iNKT17 cells is orchestrated by Runx1. Sci Rep, 7(1), 7018. PMID: 28765611.

Martin, M. D., Shan, Q., Xue, H. & Badovinac, V. P. (2017). Time and Antigen-Stimulation History Influence Memory CD8 T Cell Bystander Responses. Front Immunol, 8, 634. PMID: 28642758.

Xu, Z., Xing, S., Shan, Q., Gullicksrud, J. A., Bair, T. B., Du, Y., Liu, C. & Xue, H. (2017). Cutting Edge: ß-Catenin-Interacting Tcf1 Isoforms Are Essential for Thymocyte Survival but Dispensable for Thymic Maturation Transitions. J Immunol, 198(9), 3404-3409. PMID: 28348272.

Nish, S. A., Zens, K. D., Kratchmarov, R., Lin, W. W., Adams, W. C., Chen, Y. H., Yen, B., Rothman, N. J., Bhandoola, A., Xue, H., Farber, D. L. & Reiner, S. L. (2017). CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J Exp Med, 214(1), 39-47. PMID: 27923906.

Gullicksrud, J. A., Shan, Q. & Xue, H. (2017). Tcf1 at the crossroads of CD4+ and CD8+ T cell identity. Frontiers in Biology, 12, 83-93.

He, B., Xing, S., Chen, C., Gao, P., Teng, L., Shan, Q., Gullicksrud, J. A., Martin, M. D., Yu, S., Harty, J. T., Badovinac, V. P., Tan, K. & Xue, H. (2016). CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity, 45(6), 1341-1354. PMID: 27986453.

Lin, W. W., Nish, S. A., Yen, B., Chen, Y. H., Adams, W. C., Kratchmarov, R., Rothman, N. J., Bhandoola, A., Xue, H. & Reiner, S. L. (2016). CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination. Cell Rep, 17(7), 1773-1782. PMID: 27829149.

Yang, J., Lin, X., Pan, Y., Wang, J., Chen, P., Huang, H., Xue, H., Gao, J. & Zhong, X. P. (2016). Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses. Elife, 5, pii: e17936. PMID: 27690224.

Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., Sharpe, A. H., Freeman, G. J., Germain, R. N., Nakaya, H. I., Xue, H. & Ahmed, R. (2016). Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature, 537(7620), 417-421. PMID: 27501248.

Xing, S., Li, F., Zeng, Z., Zhao, Y., Yu, S., Shan, Q., Li, Y., Phillips, F. C., Maina, P. K., Qi, H. H., Liu, C., Zhu, J., Pope, R. M., Musselman, C. A., Zeng, C., Peng, W. & Xue, H. (2016). Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nat Immunol, 17(6), 695-703. PMID: 27111144.

Yu, S., Li, F., Xing, S., Zhao, T., Peng, W. & Xue, H. (2016). Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors. J Biol Chem, 291(21), 11148-60. PMID: 27044748.

Berga-Bolaños, R., Zhu, W. S., Steinke, F. C., Xue, H. & Sen, J. M. (2015). Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells. Mol Immunol, 68(2 Pt B), 484-9. PMID: 26490636.

Martin, M. D., Kim, M. T., Shan, Q., Sompallae, R., Xue, H., Harty, J. T. & Badovinac, V. P. (2015). Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection. PLoS Pathog, 11(10), e1005219. PMID: 26485703.

Berga-Bolaños, R., Sharma, A., Steinke, F. C., Pyaram, K., Kim, Y. H., Sultana, D. A., Fang, J. X., Chang, C. H., Xue, H., Heller, N. M. & Sen, J. M. (2015). ß-Catenin is required for the differentiation of iNKT2 and iNKT17 cells that augment IL-25-dependent lung inflammation. BMC Immunol, 16, 62. PMID: 26482437.

Khan, S. H., Martin, M. D., Starbeck-Miller, G. R., Xue, H., Harty, J. T. & Badovinac, V. P. (2015). The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses. PLoS Pathog, 11(10), e1005199. PMID: 26431533.

Yang, Q., Light, F., Harly, C., Xing, S., Ye, L., Xia, X., Wang, H., Wang, X., Yu, S., Zhou, X., Cam, M., Xue*, H. & Bhandoola*, A. (2015). TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol, 16(10), 1044-50. PMID: 26280998.

Choi, Y. S., Gullicksrud, J. A., Xing, S., Zeng, Z., Shan, Q., Li, F., Love, P. E., Peng, W., Xue*, H. & Crotty*, S. (2015). LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol, 16(9), 980-90. PMID: 26214741.

Carr, T., Krishnamoorthy, V., Yu, S., Xue, H., Kee, B. L. & Verykokakis, M. (2015). The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation. J Exp Med, 212(5), 793-807. PMID: 25897173.

Duong, K. L., Das, S., Yu, S., Barr, J. Y., Jena, S., Kim, E., Zavazava, N., Colgan, J. D., Xue, H. & Levasseur, D. N. (2014). Identification of hematopoietic-specific regulatory elements from the CD45 gene and use for lentiviral tracking of transplanted cells. Exp Hematol, 42(9), 761-72.e1-10. PMID: 24852660.

Steinke, F. C., Xue, H. (2014). From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells. Immunol Res, 59(1-3), 45-55. PMID: 24847765.

Steinke, F. C., Yu, S., Zhou, X., He, B., Yang, W., Zhou, B., Kawamoto, H., Zhu, J., Tan, K. & Xue, H. (2014). TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4(+) T cell fate and interact with Runx3 to silence Cd4 in CD8(+) T cells. Nat Immunol, 15(7), 646-56. PMID: 24836425.

Xie, W., Lynch, T. J., Liu, X., Tyler, S. R., Yu, S., Zhou, X., Luo, M., Kusner, D. M., Sun, X., Yi, Y., Zhang, Y., Goodheart, M. J., Parekh, K. R., Wells, J. M., Xue, H., Pevny, L. H. & Engelhardt, J. F. (2014). Sox2 modulates Lef-1 expression during airway submucosal gland development. Am J Physiol Lung Cell Mol Physiol, 306(7), L645-60. PMID: 24487391.

Starbeck-Miller, G. R., Xue, H. & Harty, J. T. (2014). IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo. J Exp Med, 211(1), 105-20. PMID: 24367005.

Yu, S., Xue, H. (2013). TCF-1 mediates repression of Notch pathway in T lineage-committed early thymocytes. Blood, 121(19), 4008-9. PMID: 23660861.

Yu, S., Zhou, X., Steinke, F. C., Liu, C., Chen, S. C., Zagorodna, O., Jing, X., Yokota, Y., Meyerholz, D. K., Mullighan, C. G., Knudson, C. M., Zhao, D. M. & Xue, H. (2012). The TCF-1 and LEF-1 Transcription Factors Have Cooperative and Opposing Roles in T Cell Development and Malignancy. Immunity, 37(5), 813-26. PMID: 23103132.

Zhou, X., Xue, H. (2012). Cutting edge: generation of memory precursors and functional memory CD8+ T cells depends on T cell factor-1 and lymphoid enhancer-binding factor-1. J Immunol, 189(6), 2722-6. PMID: 22875805.

Yu, S., Jing, X., Colgan, J. D., Zhao, D. M. & Xue, H. (2012). Targeting tetramer-forming GABPß isoforms impairs self-renewal of hematopoietic and leukemic stem cells. Cell Stem Cell, 11(2), 207-19. PMID: 22862946.

Yu, S., Zhou, X., Hsiao, J. J., Yu, D., Saunders, T. L. & Xue, H. (2012). Fidelity of a BAC-EGFP transgene in reporting dynamic expression of IL-7Ra in T cells. Transgenic Res, 21(1), 201-15. PMID: 21533667.

Xue, H., Zhao, D. M. (2012). Regulation of mature T cell responses by the Wnt signaling pathway. Ann N Y Acad Sci, 1247, 16-33. PMID: 22239649.

Yu, S., Cui, K., Jothi, R., Zhao, D. M., Jing, X., Zhao, K. & Xue, H. (2011). GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells. Blood, 117(7), 2166-78. PMID: 21139080.

Zhou, X., Yu, S., Zhao, D. M., Harty, J. T., Badovinac, V. P. & Xue, H. (2010). Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. Immunity, 33(2), 229-40. PMID: 20727791.

Wirth, T. C., Xue, H., Rai, D., Sabel, J. T., Bair, T., Harty, J. T. & Badovinac, V. P. (2010). Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8(+) T cell differentiation. Immunity, 33(1), 128-40. PMID: 20619696.

Yu, S., Zhao, D. M., Jothi, R. & Xue, H. (2010). Critical requirement of GABPalpha for normal T cell development. J Biol Chem, 285(14), 10179-88. PMID: 20139079.

Zhao, D. M., Yu, S., Zhou, X., Haring, J. S., Held, W., Badovinac, V. P., Harty, J. T. & Xue, H. (2010). Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J Immunol, 184(3), 1191-9. PMID: 20026746.

Wu, Z., Xue, H., Bernard, J., Zeng, R., Issakov, D., Bollenbacher-Reilley, J., Belyakov, I. M., Oh, S., Berzofsky, J. A. & Leonard, W. J. (2008). The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15Ralpha function but is not required for trans-presentation. Blood, 112(12), 4411-9. PMID: 18796634.

Jing, X., Zhao, D. M., Waldschmidt, T. J. & Xue, H. (2008). GABPbeta2 is dispensible for normal lymphocyte development but moderately affects B cell responses. J Biol Chem, 283(36), 24326-33. PMID: 18628204.

Xue, H., Jing, X., Bollenbacher-Reilley, J., Zhao, D. M., Haring, J. S., Yang, B., Liu, C., Bishop, G. A., Harty, J. T. & Leonard, W. J. (2008). Targeting the GA binding protein beta1L isoform does not perturb lymphocyte development and function. Mol Cell Biol, 28(13), 4300-9. PMID: 18426908.

Haring, J. S., Jing, X., Bollenbacher-Reilley, J., Xue, H., Leonard, W. J. & Harty, J. T. (2008). Constitutive expression of IL-7 receptor alpha does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J Immunol, 180(5), 2855-62. PMID: 18292507.

Crook, M. F., Olive, M., Xue, H., Langenickel, T. H., Boehm, M., Leonard, W. J. & Nabel, E. G. (2008). GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression. FASEB J, 22(1), 225-35. PMID: 17726090.

Xue, H., Bollenbacher-Reilley, J., Wu, Z., Spolski, R., Jing, X., Zhang, Y. C., McCoy, J. P. & Leonard, W. J. (2007). The transcription factor GABP is a critical regulator of B lymphocyte development. Immunity, 26(4), 421-31. PMID: 17442597.

Pang, L., Xue, H., Szalai, G., Wang, X., Wang, Y., Watson, D. K., Leonard, W. J., Blobel, G. A. & Poncz, M. (2006). Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins. Blood, 108(7), 2198-206. PMID: 16757682.

Leonard, W. J., Xue, H. (2006). Interleukin-7. In G. J. Laurent , S. T. Shapiro (Eds.) Encyclopedia of Respiratory Medicine. pp. 365-8. Elsevier. DOI: 10.1016/B0-12-370879-6/00478-6.

Wu, Z., Kim, H. P., Xue, H., Liu, H., Zhao, K. & Leonard, W. J. (2005). Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity. Mol Cell Biol, 25(22), 9741-52. PMID: 16260592.

Xue, H., Bollenbacher, J., Rovella, V., Tripuraneni, R., Du, Y. B., Liu, C. Y., Williams, A., McCoy, J. P. & Leonard, W. J. (2004). GA binding protein regulates interleukin 7 receptor alpha-chain gene expression in T cells. Nat Immunol, 5(10), 1036-44. PMID: 15361867.

Xue, H., Fink, D. W., Zhang, X., Qin, J., Turck, C. W. & Leonard, W. J. (2002). Serine phosphorylation of Stat5 proteins in lymphocytes stimulated with IL-2. Int Immunol, 14(11), 1263-71. PMID: 12407017.

Xue, H., Kovanen, P. E., Pise-Masison, C. A., Berg, M., Radovich, M. F., Brady, J. N. & Leonard, W. J. (2002). IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes. Proc Natl Acad Sci U S A, 99(21), 13759-64. PMID: 12354940.

Xue, H., Zhao, D. M., Suda, T., Uchida, C., Oda, T., Chida, K., Ichiyama, A. & Nakamura, H. (2000). Store depletion by caffeine/ryanodine activates capacitative Ca(2+) entry in nonexcitable A549 cells. J Biochem, 128(2), 329-36. PMID: 10920270.

Zhao, D. M., Xue, H., Chida, K., Suda, T., Oki, Y., Kanai, M., Uchida, C., Ichiyama, A. & Nakamura, H. (2000). Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells. Am J Physiol Lung Cell Mol Physiol, 278(4), L726-36. PMID: 10749750.

Ichiyama, A., Xue, H., Oda, T., Uchida, C., Sugiyama, T., Maeda-Nakai, E., Sato, K., Nagai, E., Watanabe, S. & Takayama, T. (2000). Oxalate synthesis in mammals: properties and subcellular distribution of serine:pyruvate/alanine:glyoxylate aminotransferase in the liver. Mol Urol, 4(4), 333-40. PMID: 11156700.

Xue, H., Sakaguchi, T., Fujie, M., Ogawa, H. & Ichiyama, A. (1999). Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase. J Biol Chem, 274(23), 16028-33. PMID: 10347152.

Xue, H., Fujie, M., Sakaguchi, T., Oda, T., Ogawa, H., Kneer, N. M., Lardy, H. A. & Ichiyama, A. (1999). Flux of the L-serine metabolism in rat liver. The predominant contribution of serine dehydratase. J Biol Chem, 274(23), 16020-7. PMID: 10347151.

Yu, B., Xue, H., Yang, Y., Zhao, T. & Zong, Z. (1995). A novel protein kinase C inhibitor in bovine spermatozoa and its effects on the development of fertilized ova. Biomed Res (Tokyo), 16, 155-63.