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Recent Advances in αβ T Cell Biology: Wnt Signaling, Notch Signaling, Hedgehog Signaling and Their Translational Perspective

1 Department of Orthopedic Surgery, the Second Affiliated Hospital, Fujian Medical University, Quanzhou, China;
2 Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China;
3 University of North Texas Health Science Center, Fort Worth, Texas, USA

Engagement of bioactive ligands with cell surface receptors plays critical roles in the initiation and regulation of αβ T cell development, homeostasis and functions. In the past two decades, new subpopulations of αβ T cells have been discovered. In addition, the characterization of new ligand/receptor axes has led to a better understanding of αβ T cell biology. In the current review, the phenotypic and functional properties of αβ T cell subpopulations are described, as well as the effects of three novel and well-documented signal pathways—Wnt, Notch and Hedgehog signaling—on αβ T cell development and functions are summarized. These signal pathways are initiated by the ligation of corresponding ligands with respective receptors, and this subsequently exerts a positive or negative influence on αβ T cell ontogenesis and behavior. Thorough understanding of the components of these signal pathways might shed new light on the manipulation of αβ T cell biology so as to favor the advance of diagnosis and therapy of immune disorders such as infection, tumors and autoimmune diseases.
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Keywords αβ T cells; Cell signaling; Wnt; Notch; Hedgehog

Citation: Wenping Lin, Kai Dai, Luokun Xie. Recent Advances in αβ T Cell Biology: Wnt Signaling, Notch Signaling, Hedgehog Signaling and Their Translational Perspective. AIMS Medical Science, 2016, 3(4): 312-328. doi: 10.3934/medsci.2016.4.312


  • 1. Reiner SL (2009) Decision making during the conception and career of CD4+ T cells. Nat Rev Immunol 9: 81-82.    
  • 2. Clambey ET, Davenport B, Kappler JW, et al. (2014) Molecules in medicine mini review: the alphabeta T cell receptor. J Mol Med (Berl) 92: 735-741.    
  • 3. Thompson EC (2012) Focus issue: Structure and function of lymphoid tissues. Trends Immunol 33: 255.    
  • 4. Luckheeram RV, Zhou R, Verma AD, et al. (2012) CD4+ T cells: differentiation and functions. Clin Dev Immunol 2012: 925135.
  • 5. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28: 445-489.    
  • 6. Zhang N, Bevan MJ (2011) CD8+ T cells: foot soldiers of the immune system. Immunity 35: 161-168.    
  • 7. Grabie N, Delfs MW, Westrich JR, et al. (2003) IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis. J Clin Invest 111: 671-680.    
  • 8. Starbeck-Miller GR, Xue HH, Harty JT (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: 105-120.    
  • 9. Anastas JN, Moon RT (2013) WNT signaling pathways as therapeutic targets in cancer. Nat Rev Cancer 13: 11-26.
  • 10. Moon RT, Gough NR (2016) Beyond canonical: The Wnt and beta-catenin story. Sci Signal 9: eg5.    
  • 11. Moon RT, Kohn AD, De Ferrari GV, et al. (2004) WNT and beta-catenin signaling: diseases and therapies. Nat Rev Genet 5: 691-701.    
  • 12. Klaus A, Birchmeier W (2008) Wnt signaling and its impact on development and cancer. Nat Rev Cancer 8: 387-398.    
  • 13. Clevers H, Loh KM, Nusse R (2014) Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346: 1248012.
  • 14. van de Wetering M, de Lau W, Clevers H (2002) WNT signaling and lymphocyte development. Cell 109 Suppl: S13-19.
  • 15. Pongracz J, Hare K, Harman B, et al. (2003) Thymic epithelial cells provide WNT signals to developing thymocytes. Eur J Immunol 33: 1949-1956.    
  • 16. Brunk F, Augustin I, Meister M, et al. (2015) Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development. J Immunol 195: 5261-5271.    
  • 17. Staal FJ, Meeldijk J, Moerer P, et al. (2001) Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur J Immunol 31: 285-293.
  • 18. Gounari F, Aifantis I, Khazaie K, et al. (2001) Somatic activation of beta-catenin bypasses pre-TCR signaling and TCR selection in thymocyte development. Nat Immunol 2: 863-869.    
  • 19. Weerkamp F, Baert MR, Naber BA, et al. (2006) Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules. Proc Natl Acad Sci U S A 103: 3322-3326.    
  • 20. Xu Y, Banerjee D, Huelsken J, et al. (2003) Deletion of beta-catenin impairs T cell development. Nat Immunol 4: 1177-1182.    
  • 21. Mulroy T, Xu Y, Sen JM (2003) beta-Catenin expression enhances generation of mature thymocytes. Int Immunol 15: 1485-1494.    
  • 22. Wu B, Crampton SP, Hughes CC (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26: 227-239.    
  • 23. Willinger T, Freeman T, Herbert M, et al. (2006) Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo. J Immunol 176: 1439-1446.    
  • 24. Alvarez-zavala M, Aguilar-lemarroy A, Jave-suarez LF (2015) WNT7a as a new feature of the T mature cells; expression of the WNT7a diminish in a highly activated and proliferative T cells after TCR activation and IL2 stimulus while canonical targets of WNT signaling pathway are overexpress. Front Immunol 6.
  • 25. Driessens G, Zheng Y, Locke F, et al. (2011) Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-gamma1 phosphorylation. J Immunol 186: 784-790.    
  • 26. van Loosdregt J, Fleskens V, Tiemessen MM, et al. (2013) Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 39: 298-310.    
  • 27. Keerthivasan S, Aghajani K, Dose M, et al. (2014) beta-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med 6: 225ra228.
  • 28. Yu Q, Sharma A, Oh SY, et al. (2009) T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nat Immunol 10: 992-999.    
  • 29. Notani D, Gottimukkala KP, Jayani RS, et al. (2010) Global regulator SATB1 recruits beta-catenin and regulates T(H)2 differentiation in Wnt-dependent manner. PLoS Biol 8: e1000296.    
  • 30. Prlic M, Bevan MJ (2011) Cutting edge: beta-catenin is dispensable for T cell effector differentiation, memory formation, and recall responses. J Immunol 187: 1542-1546.    
  • 31. Ding Y, Shen S, Lino AC, et al. (2008) Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med 14: 162-169.    
  • 32. Muranski P, Borman ZA, Kerkar SP, et al. (2011) Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity 35: 972-985.    
  • 33. Dai W, Liu F, Li C, et al. (2016) Blockade of Wnt/beta-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses. Mediators Inflamm 2016: 6235614.
  • 34. Lee YS, Lee KA, Yoon HB, et al. (2012) The Wnt inhibitor secreted Frizzled-Related Protein 1 (sFRP1) promotes human Th17 differentiation. Eur J Immunol 42: 2564-2573.    
  • 35. Gattinoni L, Zhong XS, Palmer DC, et al. (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15: 808-813.    
  • 36. Jeannet G, Boudousquie C, Gardiol N, et al. (2010) Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc Natl Acad Sci U S A 107: 9777-9782.    
  • 37. Zhao DM, Yu S, Zhou X, et al. (2010) Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J Immunol 184: 1191-1199.    
  • 38. Driessens G, Zheng Y, Gajewski TF (2010) Beta-catenin does not regulate memory T cell phenotype. Nat Med 16: 513-514; author reply 514-515.    
  • 39. Boudousquie C, Danilo M, Pousse L, et al. (2014) Differences in the transduction of canonical Wnt signals demarcate effector and memory CD8 T cells with distinct recall proliferation capacity. J Immunol 193: 2784-2791.    
  • 40. Richards MH, Narasipura SD, Seaton MS, et al. (2016) Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling-Dependent Manner. J Immunol 196: 317-327.    
  • 41. Taghon T, Yui MA, Pant R, et al. (2006) Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus. Immunity 24: 53-64.    
  • 42. Wendorff AA, Koch U, Wunderlich FT, et al. (2010) Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33: 671-684.    
  • 43. Koch U, Fiorini E, Benedito R, et al. (2008) Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 205: 2515-2523.    
  • 44. Anderson G, Pongracz J, Parnell S, et al. (2001) Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur J Immunol 31: 3349-3354.
  • 45. Van de Walle I, De Smet G, Gartner M, et al. (2011) Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. Blood 117: 4449-4459.    
  • 46. Jaleco AC, Neves H, Hooijberg E, et al. (2001) Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J Exp Med 194: 991-1002.    
  • 47. Minter LM, Turley DM, Das P, et al. (2005) Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol 6: 680-688.    
  • 48. Jurynczyk M, Jurewicz A, Raine CS, et al. (2008) Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase C theta and attenuates experimental autoimmune encephalomyelitis. J Immunol 180: 2634-2640.    
  • 49. Auderset F, Schuster S, Coutaz M, et al. (2012) Redundant Notch1 and Notch2 signaling is necessary for IFNgamma secretion by T helper 1 cells during infection with Leishmania major. PLoS Pathog 8: e1002560.    
  • 50. Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89: 587-596.    
  • 51. Elyaman W, Bassil R, Bradshaw EM, et al. (2012) Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36: 623-634.    
  • 52. Bailis W, Yashiro-Ohtani Y, Fang TC, et al. (2013) Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity 39: 148-159.    
  • 53. Anastasi E, Campese AF, Bellavia D, et al. (2003) Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes. J Immunol 171: 4504-4511.    
  • 54. Campese AF, Grazioli P, Colantoni S, et al. (2009) Notch3 and pTalpha/pre-TCR sustain the in vivo function of naturally occurring regulatory T cells. Int Immunol 21: 727-743.    
  • 55. Barbarulo A, Grazioli P, Campese AF, et al. (2011) Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. J Immunol 186: 6199-6206.    
  • 56. Charbonnier LM, Wang S, Georgiev P, et al. (2015) Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol 16: 1162-1173.    
  • 57. Hue S, Kared H, Mehwish Y, et al. (2012) Notch activation on effector T cells increases their sensitivity to Treg cell-mediated suppression through upregulation of TGF-betaRII expression. Eur J Immunol 42: 1796-1803.    
  • 58. Wong KK, Carpenter MJ, Young LL, et al. (2003) Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism. J Clin Invest 112: 1741-1750.    
  • 59. Riella LV, Ueno T, Batal I, et al. (2011) Blockade of Notch ligand delta1 promotes allograft survival by inhibiting alloreactive Th1 cells and cytotoxic T cell generation. J Immunol 187: 4629-4638.    
  • 60. Maekawa Y, Minato Y, Ishifune C, et al. (2008) Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat Immunol 9: 1140-1147.    
  • 61. Sugimoto K, Maekawa Y, Kitamura A, et al. (2010) Notch2 signaling is required for potent antitumor immunity in vivo. J Immunol 184: 4673-4678.    
  • 62. Sierra RA, Thevenot P, Raber PL, et al. (2014) Rescue of notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol Res 2: 800-811.    
  • 63. Backer RA, Helbig C, Gentek R, et al. (2014) A central role for Notch in effector CD8(+) T cell differentiation. Nat Immunol 15: 1143-1151.    
  • 64. Mathieu M, Duval F, Daudelin JF, et al. (2015) The Notch signaling pathway controls short-lived effector CD8+ T cell differentiation but is dispensable for memory generation. J Immunol 194: 5654-5662.    
  • 65. Briscoe J, Therond PP (2013) The mechanisms of Hedgehog signaling and its roles in development and disease. Nat Rev Mol Cell Biol 14: 416-429.
  • 66. Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signaling across the metazoa. Nat Rev Genet 12: 393-406.    
  • 67. Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22: 2454-2472.    
  • 68. Outram SV, Varas A, Pepicelli CV, et al. (2000) Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte. Immunity 13: 187-197.    
  • 69. Shah DK, Hager-Theodorides AL, Outram SV, et al. (2004) Reduced thymocyte development in sonic hedgehog knockout embryos. J Immunol 172: 2296-2306.    
  • 70. El Andaloussi A, Graves S, Meng F, et al. (2006) Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus. Nat Immunol 7: 418-426.    
  • 71. Sacedon R, Varas A, Hernandez-Lopez C, et al. (2003) Expression of hedgehog proteins in the human thymus. J Histochem Cytochem 51: 1557-1566.    
  • 72. Hager-Theodorides AL, Dessens JT, Outram SV, et al. (2005) The transcription factor Gli3 regulates differentiation of fetal CD4- CD8- double-negative thymocytes. Blood 106: 1296-1304.    
  • 73. Stewart GA, Lowrey JA, Wakelin SJ, et al. (2002) Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells. J Immunol 169: 5451-5457.    
  • 74. Lowrey JA, Stewart GA, Lindey S, et al. (2002) Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes. J Immunol 169: 1869-1875.    
  • 75. Rowbotham NJ, Hager-Theodorides AL, Cebecauer M, et al. (2007) Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation. Blood 109: 3757-3766.    
  • 76. Furmanski AL, Barbarulo A, Solanki A, et al. (2015) The transcriptional activator Gli2 modulates T-cell receptor signaling through attenuation of AP-1 and NFkappaB activity. J Cell Sci 128: 2085-2095.    
  • 77. Michel KD, Uhmann A, Dressel R, et al. (2013) The hedgehog receptor patched1 in T cells is dispensable for adaptive immunity in mice. PLoS One 8: e61034.    
  • 78. de la Roche M, Ritter AT, Angus KL, et al. (2013) Hedgehog signaling controls T cell killing at the immunological synapse. Science 342: 1247-1250.    
  • 79. Ye H, Zhang J, Wang J, et al. (2015) CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case-control study. Arthritis Res Ther 17: 76.    
  • 80. Weng AP, Ferrando AA, Lee W, et al. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269-271.    
  • 81. Tosello V, Ferrando AA (2013) The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol 4: 199-210.    
  • 82. Jiao Z, Wang W, Hua S, et al. (2014) Blockade of Notch signaling ameliorates murine collagen-induced arthritis via suppressing Th1 and Th17 cell responses. Am J Pathol 184: 1085-1093.    
  • 83. Kijima M, Iwata A, Maekawa Y, et al. (2009) Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells. J Immunol 182: 3566-3572.    
  • 84. Sodsai P, Hirankarn N, Avihingsanon Y, et al. (2008) Defects in Notch1 upregulation upon activation of T Cells from patients with systemic lupus erythematosus are related to lupus disease activity. Lupus 17: 645-653.    
  • 85. Rauen T, Grammatikos AP, Hedrich CM, et al. (2012) cAMP-responsive element modulator alpha (CREMalpha) contributes to decreased Notch-1 expression in T cells from patients with active systemic lupus erythematosus (SLE). J Biol Chem 287: 42525-42532.    
  • 86. Bassil R, Zhu B, Lahoud Y, et al. (2011) Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J Immunol 187: 2322-2328.    
  • 87. Dagklis A, Pauwels D, Lahortiga I, et al. (2015) Hedgehog pathway mutations in T-cell acute lymphoblastic leukemia. Haematologica 100: e102-105.    
  • 88. Gonzalez-Gugel E, Villa-Morales M, Santos J, et al. (2013) Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development. Carcinogenesis 34: 902-908.    


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