Memory T cell Biology

During an acute viral or bacterial infection, naïve T cells can differentiate into multiple types of effector and memory T cells that help to mediate pathogen clearance and provide long-term protective immunity. The main goal of our research in the lab is to elucidate how TCR and cytokine signaling and their downstream transcriptional programs regulate pathogen-specific T cells to proliferate, differentiate into either short-lived effector cells or long-lived memory cells.

Activated T cells receive and integrate a myriad of signals from their microenvironment. These signals differ in type, quality, quantity and duration, and could have significant impact on T cell activation, differentiation and survival. One area of our research interest is to study how these different signals cooperate with each other to regulate T cell expansion and acquisition of their effector function, and concurrently differ in their activities to control the short- or long-term fate decision. We aim to further investigate where and when these signals are produced and emanated, which will help to better understand how the distinct cellular niches influence effector and memory T cell fate decision and functional maturation. 

JAK-STAT pathways are the important mediators to transmit extracellular signals into transcriptional programs that ultimately regulate effector and memory T cell differentiation, survival and homeostasis. Our recent work has demonstrated that STAT4 and STAT3 largely promote distinct cell fate commitment, and terminal effector versus memory cells respectively. A major focus in the lab currently is to better define how these different STAT pathways act in a synergistic or divergent fashion to regulate both terminal cell-fate commitment and permit plasticity in effector and memory T cells.

• NIAID, 1R01AI125741, The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses, 05/16/2016 - 04/30/2021, Role: PI
• MCW Cancer Center and the Wisconsin Breast Cancer Showhouse for a Cure, Inc., Independent Research Seed Grant, Harnessing Dual-Specific T Cells in Breast Cancer Immunotherapy, 05/01/2014 - 10/31/2016, Role: PI
• MCW Cancer Center and the American Cancer Society, Pilot Research Project Grant, The Role of IL-24-BATF Axis in Promoting Anti-Tumor Immunity,  11/01/2014 - 10/31/2016, Role: PI
• MCW Cancer Center and the Ann's Hope Award for Melanoma Cancer Research, A Multi-pronged Immunotherapy to Fight Melanoma, 05/01/2015 - 07/31/2016, Role: PI

1. Darrah EJ, Jondle CN, Johnson KE, Xin G, Lange PT, Cui W, Olteanu H, Tarakanova VL. Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses. J Virol. 2019 Apr 3;93(8). pii: e01760-18. 
2. Chen Y, Zander R, Khatun A, Schauder DM, Cui W. Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation. Front Immunol. 2018 Dec 7;9:2826. PMID: 30581433 
3. Xin G, Zander R, Schauder DM, Chen Y, Weinstein JS, Drobyski WR, Tarakanova V, Craft J, Cui W. Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection. Nat Commun. 2018 Nov 28;9(1):5037. PMID: 30487586  
4. Newman DK, Fu G, McOlash L, Schauder D, Newman PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Frontline Science: PECAM-1 (CD31) expression in naïve and memory, but not acutely activated, CD8⁺ T cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: 30063264  
5. Wesley EM, Xin G, McAllister D, Malarkannan S, Newman DK, Dwinell MB, Cui W, Johnson BD, Riese MJ. Diacylglycerol kinase ζ (DGKζ) and Casitas b-lineage proto-oncogene b-deficient mice have similar functional outcomes in T cells but DGKζ-deficient mice have increased T cell activation and tumor clearance. Immunohorizons. 2018 Apr 1;2(4):107-118. PMID: 30027154 
6. Xin G, Schauder DM, Zander R, Cui W. Two is better than one: advances in pathogen-boosted immunotherapy and adoptive T-cell therapy. Immunotherapy. 2017 Sep;9(10):837-849. PMID: 28877635
7. Zander R, Cui W. The power of combining adoptive cell therapy (ACT) and pathogen-boosted vaccination to treat solid tumors.Hum Vaccin Immunother. 2017 Oct 3;13(10):2269-2271. PMCID: PMC5647994.
8. Darrah EJ, Kulinski JM, Mboko WP, Xin G, Malherbe LP, Gauld SB, Cui W, Tarakanova VL. B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection. J Virol. 2017 Sep 12;91(19). pii: e01103-17. PMCID: PMC5599758.
9. Chen Y, Huang W, Yang M, Xin G, Cui W, Xie Z, Silverstein RL. Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1462-1469. PMCID: PMC5532064.
10. Xin G, Schauder DM, Jing W, Jiang A, Joshi NS, Johnson B, Cui W. Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):740-745. PMCID: PMC5278465.
11. Kutty RG, Xin G, Schauder DM, Cossette SM, Bordas M, Cui W, Ramchandran R. Dual Specificity Phosphatase 5 Is Essential for T Cell Survival. PLoS One. 2016 Dec 9;11(12):e0167246. PMCID: PMC5147890.
12. Mboko WP, Olteanu H, Ray A, Xin G, Darrah EJ, Kumar SN, Kulinski JM, Cui W, Dittel BN, Gauld SB, Tarakanova VL. Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus. J Virol. 2015 Dec 30;90(6):2818-29. PMCID: PMC4810652.
13. Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z, Chen Y, Esplugues E, Wen R, Wang D, Parish IA, Zajac AJ, Craft J, Cui W. A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control. Cell Rep. 2015 Nov 10;13(6):1118-1124. PMCID: PMC4859432.
14. Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM. Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol. 2015 Aug;16(8):871-9. PMCID: PMC4713030.
15. Fu C, Liang X, Cui W, Ober-Blöbaum JL, Vazzana J, Shrikant PA, Lee KP, Clausen BE, Mellman I, Jiang A. β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2823-8. PMCID: PMC4352820.
16. Kang H, Kerloc'h A, Rotival M, Xu X, Zhang Q, D'Souza Z, Kim M, Scholz JC, Ko JH, Srivastava PK, Genzen JR, Cui W, Aitman TJ, Game L, Melvin JE, Hanidu A, Dimock J, Zheng J, Souza D, Behera AK, Nabozny G, Cook HT, Bassett JH, Williams GR, Li J, Vignery A, Petretto E, Behmoaras J. Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease. Cell Rep. 2014 Aug 21;8(4):1210-24. PMCID: PMC4471813.
17. Parish IA, Marshall HD, Staron MM, Lang PA, Brüstle A, Chen JH, Cui W, Tsui YC, Perry C, Laidlaw BJ, Ohashi PS, Weaver CT, Kaech SM. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J Clin Invest. 2014 Aug;124(8):3455-68. PMCID: PMC4109559.
18. Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM. TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation. J Immunol. 2014 May 1;192(9):4221-32. PMCID: PMC4071140.
19. Liang X, Fu C, Cui W, Ober-Blöbaum JL, Zahner SP, Shrikant PA, Clausen BE, Flavell RA, Mellman I, Jiang A. β-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8⁺ T cells. J Leukoc Biol. 2014 Jan;95(1):179-90. PMID: 24023259.
20. Dominguez C, Cui W. Inside out: decoding the transcriptome of effector and memory T cells. Immunol Cell Biol. 2013 Jul;91(6):389-90. PMID: 23628806.
21. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012 Nov;12(11):749-61. PMCID: PMC4137483.
22. Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM, Fahmy TM. Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials. 2012 Jun;33(19):4957-64. PMCID: PMC5724530.
23. Wang X, Li H, Matte-Martone C, Cui W, Li N, Tan HS, Roopenian D, Shlomchik WD. Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation. Blood. 2011 Dec 8;118(24):6426-37. PMCID: PMC3236124.
24. Li N, Matte-Martone C, Zheng H, Cui W, Venkatesan S, Tan HS, McNiff J, Demetris AJ, Roopenian D, Kaech S, Shlomchik WD. Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution. Blood. 2011 Nov 24;118(22):5965-76. PMCID: PMC3228506.
25. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity. 2011 Nov 23;35(5):792-805.  PMCID: PMC3431922.
26. Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rutishauser R, Cui W, Kleinstein SH, Craft J, Kaech SM. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection.Immunity. 2011 Oct 28;35(4):633-46. PMCID: PMC3444169.
27. Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW, Kaech SM. Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol. 2011 Oct 15;187(8):4068-76. PMCID: PMC3991478.
28. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, Liu Y, Kaech SM. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16601-6. PMCID: PMC2944719.
29. Demento SL, Bonafé N, Cui W, Kaech SM, Caplan MJ, Fikrig E, Ledizet M, Fahmy TM. TLR9-targeted biodegradable nanoparticles as immunization vectors protect against West Nile encephalitis. J Immunol. 2010 Sep 1;185(5):2989-97. PMCID: PMC3753007.
30. Cui W, Kaech SM. Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol Rev. 2010 Jul;236:151-66. PMCID: PMC4380273.
31. Carlson J, Cui W, Zhang Q, Xu X, Mercan F, Bennett AM, Vignery A. Role of MKP-1 in osteoclasts and bone homeostasis. Am J Pathol. 2009 Oct;175(4):1564-73. PMCID: PMC2751553.
32. Cui W, Joshi NS, Jiang A, Kaech SM. Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation. Vaccine. 2009 Mar 26;27(15):2177-87. PMCID: PMC2803112.
33. Rahman AH, Cui W, Larosa DF, Taylor DK, Zhang J, Goldstein DR, Wherry EJ, Kaech SM, Turka LA. MyD88 plays a critical T cell-intrinsic role in supporting CD8 T cell expansion during acute lymphocytic choriomeningitis virus infection. J Immunol. 2008 Sep 15;181(6):3804-10. PMCID: PMC2835404.
34. Jiang A, Bloom O, Ono S, Cui W, Unternaehrer J, Jiang S, Whitney JA, Connolly J, Banchereau J, Mellman I. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity. 2007 Oct;27(4):610-24. Epub 2007 Oct 11. PMCID: PMC2151979.
35. Cui W, Cuartas E, Ke J, Zhang Q, Einarsson HB, Sedgwick JD, Li J, Vignery A. CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14436-41. Epub 2007 Aug 28. PMCID: PMC1955461.
36. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007 Aug;27(2):281-95. PMCID: PMC2034442.
37. Cui W, Ke JZ, Zhang Q, Ke HZ, Chalouni C, Vignery A. The intracellular domain of CD44 promotes the fusion of macrophages.Blood. 2006 Jan 15;107(2):796-805. Epub 2005 Sep 29.  PMCID: PMC1473173.
38. Li H, Cuartas E, Cui W, Choi Y, Crawford TD, Ke HZ, Kobayashi KS, Flavell RA, Vignery A. IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation. J Exp Med. 2005 Apr 4;201(7):1169-77. PMCID: PMC2213136.
39. Cui WG, Zhao H, Song YZ, Zhang J, Zhang LG, Shi JD, Qiang WM. Clinical significance of expression of PSA, hK2, PSMA in the peripheral blood of patients with prostate cancer. Zhonghua Zhong Liu Za Zhi. 2004 Aug;26(8):479-81. Chinese. PubMed PMID: 15555338.