The signaling symphony: T cell receptor tunes cytokine-mediated t cell differentiation

Journal of Leukocyte Biology

Volumn 97, Issue 3, 2015, Pages 477-485

  Huang, Weishan ^a   August, Avery ^a  

^a Department of Obstetrics Gynecology   (United States)

Author keywords

Effector function; Homeostasis; Pathway crosstalk; Proliferation; Signal rheostat

Indexed keywords

INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 7; T LYMPHOCYTE RECEPTOR; CYTOKINE; LYMPHOCYTE ANTIGEN RECEPTOR;

AUTOIMMUNITY; CALCIUM CELL LEVEL; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DEATH; CELL MATURATION; CYTOKINE PRODUCTION; CYTOKINE RESPONSE; HOMEOSTASIS; HUMAN; LYMPHOCYTE DIFFERENTIATION; NEGATIVE FEEDBACK; NONHUMAN; PRE T LYMPHOCYTE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TRANSCRIPTION INITIATION; ANIMAL; CELL DIFFERENTIATION; CYTOLOGY; IMMUNOLOGY; METABOLISM;

MURINAE;

ANIMALS; CELL DIFFERENTIATION; CYTOKINES; HOMEOSTASIS; HUMANS; RECEPTORS, ANTIGEN, T-CELL; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84929163178     PISSN: 07415400     EISSN: 19383673     Source Type: Journal    
DOI: 10.1189/jlb.1RI0614-293R     Document Type: Review

References (129)

1. Anderson, G., Moore, N. C., Owen, J. J., Jenkinson, E. J. (1996) Cellular interactions in thymocyte development. Annu. Rev. Immunol. 14, 73–99.
2. Surh, C. D., Sprent, J. (2008) Homeostasis of naive and memory T cells. Immunity 29, 848–862.
3. Schluns, K. S., Lefrançois, L. (2003) Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279.
4. Zhu, J., Paul, W. E. (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol. Rev. 238, 247–262.
5. O’Garra, A. (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8, 275–283.
6. Rochman, Y., Spolski, R., Leonard, W. J. (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat. Rev. Immunol. 9, 480–490.
7. Kannan, A., Huang, W., Huang, F., August, A. (2012) Signal transduction via the T cell antigen receptor in naïve and effector/ memory T cells. Int. J. Biochem. Cell Biol. 44, 2129–2134.
8. Irving, B. A., Weiss, A. (1991) The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64, 891–901.
9. Letourneur, F., Klausner, R. D. (1992) Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. Science 255, 79–82.
10. Chan, A. C., Iwashima, M., Turck, C. W., Weiss, A. (1992) ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71, 649–662.
11. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P., Samelson, L. E. (1998) LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83–92.
12. Bubeck Wardenburg, J., Fu, C., Jackman, J. K., Flotow, H., Wilkinson, S. E., Williams, D. H., Johnson, R., Kong, G., Chan, A. C., Findell, P. R. (1996) Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J. Biol. Chem. 271, 19641–19644.
13. Smith-Garvin, J. E., Koretzky, G. A., Jordan, M. S. (2009) T cell activation. Annu. Rev. Immunol. 27, 591–619.
14. August, A., Sadra, A., Dupont, B., Hanafusa, H. (1997) Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc. Natl. Acad. Sci. USA 94, 11227–11232.
15. Ching, K. A., Grasis, J. A., Tailor, P., Kawakami, Y., Kawakami, T., Tsoukas, C. D. (2000) TCR/CD3-induced activation and binding of Emt/Itk to linker of activated T cell complexes: requirement for the Src homology 2 domain. J. Immunol. 165, 256–262.
16. Bunnell, S. C., Diehn, M., Yaffe, M. B., Findell, P. R., Cantley, L. C., Berg, L. J. (2000) Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J. Biol. Chem. 275, 2219–2230.
17. Jordan, M. S., Smith, J. E., Burns, J. C., Austin, J. E., Nichols, K. E., Aschenbrenner, A. C., Koretzky, G. A. (2008) Complementation in trans of altered thymocyte development in mice expressing mutant forms of the adaptor molecule SLP76. Immunity 28, 359–369.
18. Gordon, S. M., Carty, S. A., Kim, J. S., Zou, T., Smith-Garvin, J., Alonzo, E. S., Haimm, E., Sant’Angelo, D. B., Koretzky, G. A., Reiner, S. L., Jordan, M. S. (2011) Requirements for eomesodermin and promyelocytic leukemia zinc finger in the development of innate-like CD8+ T cells. J. Immunol. 186, 4573–4578.
19. August, A., Ragin, M. J. (2012) Regulation of T-cell responses and disease by tec kinase Itk. Int. Rev. Immunol. 31, 155–165.
20. Berg, L. J., Finkelstein, L. D., Lucas, J. A., Schwartzberg, P. L. (2005) Tec family kinases in T lymphocyte development and function. Annu. Rev. Immunol. 23, 549–600.
21. Andreotti, A. H., Schwartzberg, P. L., Joseph, R. E., Berg, L. J. (2010) T-Cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harb. Perspect. Biol. 2, a002287.
22. Joseph, R. E., Min, L., Xu, R., Musselman, E. D., Andreotti, A. H. (2007) A remote substrate docking mechanism for the tec family tyrosine kinases. Biochemistry 46, 5595–5603.
23. Perez-Villar, J. J., Kanner, S. B. (1999) Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes. J. Immunol. 163, 6435–6441.
24. Hogan, P. G., Lewis, R. S., Rao, A. (2010) Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533.
25. Fowell, D. J., Shinkai, K., Liao, X. C., Beebe, A. M., Coffman, R. L., Littman, D. R., Locksley, R. M. (1999) Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity 11, 399–409.
26. Schaeffer, E. M., Debnath, J., Yap, G., McVicar, D., Liao, X. C., Littman, D. R., Sher, A., Varmus, H. E., Lenardo, M. J., Schwartzberg, P. L. (1999) Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science 284, 638–641.
27. Liu, K. Q., Bunnell, S. C., Gurniak, C. B., Berg, L. J. (1998) T Cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. J. Exp. Med. 187, 1721–1727.
28. Wegener, E., Oeckinghaus, A., Papadopoulou, N., Lavitas, L., Schmidt- Supprian, M., Ferch, U., Mak, T. W., Ruland, J., Heissmeyer, V., Krappmann, D. (2006) Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation. Mol. Cell 23, 13–23.
29. Narayan, P., Holt, B., Tosti, R., Kane, L. P. (2006) CARMA1 is required for Akt-mediated NF-kappaB activation in T cells. Mol. Cell. Biol. 26, 2327–2336.
30. Blonska, M., Lin, X. (2011) NF-kB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 21, 55–70.
31. Yamashita, M., Kimura, M., Kubo, M., Shimizu, C., Tada, T., Perlmutter, R. M., Nakayama, T. (1999) T Cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation. Proc. Natl. Acad. Sci. USA 96, 1024–1029.
32. Yamashita, M., Katsumata, M., Iwashima, M., Kimura, M., Shimizu, C., Kamata, T., Shin, T., Seki, N., Suzuki, S., Taniguchi, M., Nakayama, T. (2000) T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex. J. Exp. Med. 191, 1869–1879.
33. Gomez-Rodriguez, J., Sahu, N., Handon, R., Davidson, T. S., Anderson, S. M., Kirby, M. R., August, A., Schwartzberg, P. L. (2009) Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity 31, 587–597.
34. Gomez-Rodriguez, J., Wohlfert, E. A., Handon, R., Meylan, F., Wu, J. Z., Anderson, S. M., Kirby, M. R., Belkaid, Y., Schwartzberg, P. L. (2014) Itkmediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J. Exp. Med. 211, 529–543.
35. Gottschalk, R. A., Corse, E., Allison, J. P. (2010) TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701–1711.
36. Turner, M. S., Kane, L. P., Morel, P. A. (2009) Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J. Immunol. 183, 4895–4903.
37. Sauer, S., Bruno, L., Hertweck, A., Finlay, D., Leleu, M., Spivakov, M., Knight, Z. A., Cobb, B. S., Cantrell, D., O’Connor, E., Shokat, K. M., Fisher, A. G., Merkenschlager, M. (2008) T Cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA 105, 7797–7802.
38. Park, J. H., Adoro, S., Lucas, P. J., Sarafova, S. D., Alag, A. S., Doan, L. L., Erman, B., Liu, X., Ellmeier, W., Bosselut, R., Feigenbaum, L., Singer, A. (2007) ‘Coreceptor tuning’: cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat. Immunol. 8, 1049–1059.
39. Huang, W., Huang, F., Kannan, A. K., Hu, J., August, A. (2014) ITK tunes IL-4-induced development of innate memory CD8+ T cells in a gd T and invariant NKT cell-independent manner. J. Leukoc. Biol. 96, 55–63.
40. Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M. (2008) Regulatory T cells and immune tolerance. Cell 133, 775–787.
41. Josefowicz, S. Z., Lu, L. F., Rudensky, A. Y. (2012) Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564.
42. Belkaid, Y., Tarbell, K. (2009) Regulatory T cells in the control of hostmicroorganism interactions (*). Annu. Rev. Immunol. 27, 551–589.
43. Curotto de Lafaille, M. A., Lafaille, J. J. (2009) Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635.
44. Tai, X., Erman, B., Alag, A., Mu, J., Kimura, M., Katz, G., Guinter, T., McCaughtry, T., Etzensperger, R., Feigenbaum, L., Singer, D. S., Singer, A. (2013) Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38, 1116–1128.
45. Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R., Farrar, M. A. (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290.
46. Yao, Z., Kanno, Y., Kerenyi, M., Stephens, G., Durant, L., Watford, W. T., Laurence, A., Robinson, G. W., Shevach, E. M., Moriggl, R., Hennighausen, L., Wu, C., O’Shea, J. J. (2007) Nonredundant roles for Stat5a/b in directly regulating Foxp 3. Blood 109, 4368–4375.
47. Zorn, E., Nelson, E. A., Mohseni, M., Porcheray, F., Kim, H., Litsa, D., Bellucci, R., Raderschall, E., Canning, C., Soiffer, R. J., Frank, D. A., Ritz, J. (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579.
48. Burchill, M. A., Yang, J., Vang, K. B., Moon, J. J., Chu, H. H., Lio, C. W., Vegoe, A. L., Hsieh, C. S., Jenkins, M. K., Farrar, M. A. (2008) Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112–121.
49. Fu, S., Zhang, N., Yopp, A. C., Chen, D., Mao, M., Chen, D., Zhang, H., Ding, Y., Bromberg, J. S. (2004) TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 2 precursors. Am. J. Transplant. 4, 1614–1627.
50. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M. L., Greene, M. I., Tone, M. (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202.
51. Davidson, T. S., DiPaolo, R. J., Andersson, J., Shevach, E. M. (2007) Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178, 4022–4026.
52. Zheng, S. G., Gray, J. D., Ohtsuka, K., Yamagiwa, S., Horwitz, D. A. (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD252 precursors. J. Immunol. 169, 4183–4189.
53. Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., Wahl, S. M. (2003) Conversion of peripheral CD4+CD252 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp 3. J. Exp. Med. 198, 1875–1886.
54. Lerman, M. A., Larkin III, J., Cozzo, C., Jordan, M. S., Caton, A. J. (2004) CD4+ CD25+ regulatory T cell repertoire formation in response to varying expression of a neo-self-antigen. J. Immunol. 173, 236–244.
55. Cozzo Picca, C., Simons, D. M., Oh, S., Aitken, M., Perng, O. A., Mergenthaler, C., Kropf, E., Erikson, J., Caton, A. J. (2011) CD4⁺CD25⁺Foxp3⁺ regulatory T cell formation requires more specific recognition of a self-peptide than thymocyte deletion. Proc. Natl. Acad. Sci. USA 108, 14890–14895.
56. Hsieh, C. S., Liang, Y., Tyznik, A. J., Self, S. G., Liggitt, D., Rudensky, A. Y. (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277.
57. Moran, A. E., Holzapfel, K. L., Xing, Y., Cunningham, N. R., Maltzman, J. S., Punt, J., Hogquist, K. A. (2011) T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289.
58. Ohkura, N., Hamaguchi, M., Morikawa, H., Sugimura, K., Tanaka, A., Ito, Y., Osaki, M., Tanaka, Y., Yamashita, R., Nakano, N., Huehn, J., Fehling, H. J., Sparwasser, T., Nakai, K., Sakaguchi, S. (2012) T Cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799.
59. Morikawa, H., Ohkura, N., Vandenbon, A., Itoh, M., Nagao-Sato, S., Kawaji, H., Lassmann, T., Carninci, P., Hayashizaki, Y., Forrest, A. R., Standley, D. M., Date, H., Sakaguchi, S.; FANTOM Consortium. (2014) Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl. Acad. Sci. USA 111, 5289–5294.
60. Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., von Boehmer, H. (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227.
61. Zou, T., Satake, A., Corbo-Rodgers, E., Schmidt, A. M., Farrar, M. A., Maltzman, J. S., Kambayashi, T. (2012) Cutting edge: IL-2 signals determine the degree of TCR signaling necessary to support regulatory T cell proliferation in vivo. J. Immunol. 189, 28–32.
62. Tischner, D., Wiegers, G. J., Fiegl, H., Drach, M., Villunger, A. (2012) Mutual antagonism of TGF-beta and interleukin-2 in cell survival and lineage commitment of induced regulatory T cells. Cell Death Differ. 19, 1277–1287.
63. Harada, Y., Harada, Y., Elly, C., Ying, G., Paik, J. H., DePinho, R. A., Liu, Y. C. (2010) Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 207, 1381–1391.
64. Marson, A., Kretschmer, K., Frampton, G. M., Jacobsen, E. S., Polansky, J. K., MacIsaac, K. D., Levine, S. S., Fraenkel, E., von Boehmer, H., Young, R. A. (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935.
65. Mahmud, S. A., Manlove, L. S., Schmitz, H. M., Xing, Y., Wang, Y., Owen, D. L., Schenkel, J. M., Boomer, J. S., Green, J. M., Yagita, H., Chi, H., Hogquist, K. A., Farrar, M. A. (2014) Costimulation via the tumornecrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15, 473–481.
66. Caton, A. J., Kropf, E., Simons, D. M., Aitken, M., Weissler, K. A., Jordan, M. S. (2014) Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3(+) Treg-cell formation. Eur. J. Immunol. 44, 785–793.
67. Hwang, S., Song, K. D., Lesourne, R., Lee, J., Pinkhasov, J., Li, L., El- Khoury, D., Love, P. E. (2012) Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease. J. Exp. Med. 209, 1781–1795.
68. Huang, W., Jeong, A. R., Kannan, A. K., Huang, L., August, A. (2014) IL-2-inducible T cell kinase tunes T regulatory cell development and is required for suppressive function. J. Immunol. 193, 2267–2272.
69. Bensinger, S. J., Walsh, P. T., Zhang, J., Carroll, M., Parsons, R., Rathmell, J. C., Thompson, C. B., Burchill, M. A., Farrar, M. A., Turka, L. A. (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J. Immunol. 172, 5287–5296.
70. Schluns, K. S., Kieper, W. C., Jameson, S. C., Lefrançois, L. (2000) Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432.
71. Sprent, J., Surh, C. D. (2011) Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484.
72. Fry, T. J., Mackall, C. L. (2001) Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 22, 564–571.
73. Khaled, A. R., Durum, S. K. (2002) The role of cytokines in lymphocyte homeostasis. Biotechniques 33, (Suppl), S40–S45.
74. Tan, J. T., Dudl, E., LeRoy, E., Murray, R., Sprent, J., Weinberg, K. I., Surh, C. D. (2001) IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA 98, 8732–8737.
75. Mazzucchelli, R., Durum, S. K. (2007) Interleukin-7 receptor expression: intelligent design. Nat. Rev. Immunol. 7, 144–154.
76. Park, J. H., Yu, Q., Erman, B., Appelbaum, J. S., Montoya-Durango, D., Grimes, H. L., Singer, A. (2004) Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21, 289–302.
77. Kimura, M. Y., Pobezinsky, L. A., Guinter, T. I., Thomas, J., Adams, A., Park, J. H., Tai, X., Singer, A. (2013) IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death. Nat. Immunol. 14, 143–151.
78. Takada, K., Jameson, S. C. (2009) Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J. Exp. Med. 206, 2253–2269.
79. Liao, X. C., Littman, D. R. (1995) Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 3, 757–769.
80. Schaeffer, E. M., Broussard, C., Debnath, J., Anderson, S., McVicar, D. W., Schwartzberg, P. L. (2000) Tec family kinases modulate thresholds for thymocyte development and selection. J. Exp. Med. 192, 987–1000.
81. Lucas, J. A., Atherly, L. O., Berg, L. J. (2002) The absence of Itk inhibits positive selection without changing lineage commitment. J. Immunol. 168, 6142–6151.
82. Atherly, L. O., Brehm, M. A., Welsh, R. M., Berg, L. J. (2006) Tec kinases Itk and Rlk are required for CD8+ T cell responses to virus infection independent of their role in CD4+ T cell help. J. Immunol. 176, 1571–1581.
83. Dubois, S., Waldmann, T. A., Müller, J. R. (2006) ITK and IL-15 support two distinct subsets of CD8+ T cells. Proc. Natl. Acad. Sci. USA 103, 12075–12080.
84. Broussard, C., Fleischacker, C., Horai, R., Chetana, M., Venegas, A. M., Sharp, L. L., Hedrick, S. M., Fowlkes, B. J., Schwartzberg, P. L. (2006) Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25, 93–104.
85. Hu, J., Sahu, N., Walsh, E., August, A. (2007) Memory phenotype CD8+ T cells with innate function selectively develop in the absence of active Itk. Eur. J. Immunol. 37, 2892–2899.
86. Huang, W., Hu, J., August, A. (2013) Cutting edge: innate memory CD8+ T cells are distinct from homeostatic expanded CD8+ T cells and rapidly respond to primary antigenic stimuli. J. Immunol. 190, 2490–2494.
87. Huang, W., Qi, Q., Hu, J., Huang, F., Laufer, T. M., August, A. (2014) Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation. J. Immunol. 192, 3435–3441.
88. Weinreich, M. A., Odumade, O. A., Jameson, S. C., Hogquist, K. A. (2010) T Cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat. Immunol. 11, 709–716.
89. Lai, D., Zhu, J., Wang, T., Hu-Li, J., Terabe, M., Berzofsky, J. A., Clayberger, C., Krensky, A. M. (2011) KLF13 sustains thymic memorylike CD8(+) T cells in BALB/c mice by regulating IL-4-generating invariant natural killer T cells. J. Exp. Med. 208, 1093–1103.
90. Felices, M., Berg, L. J. (2008) The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival. J. Immunol. 180, 3007–3018.
91. Gadue, P., Stein, P. L. (2002) NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. J. Immunol. 169, 2397–2406.
92. Au-Yeung, B. B., Fowell, D. J. (2007) A key role for Itk in both IFN gamma and IL-4 production by NKT cells. J. Immunol. 179, 111–119.
93. Qi, Q., Xia, M., Hu, J., Hicks, E., Iyer, A., Xiong, N., August, A. (2009) Enhanced development of CD4+ gammadelta T cells in the absence of Itk results in elevated IgE production. Blood 114, 564–571.
94. Felices, M., Yin, C. C., Kosaka, Y., Kang, J., Berg, L. J. (2009) Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo. Proc. Natl. Acad. Sci. USA 106, 8308–8313.
95. Prince, A. L., Watkin, L. B., Yin, C. C., Selin, L. K., Kang, J., Schwartzberg, P. L., Berg, L. J. (2014) Innate PLZF+CD4+ ab T cells develop and expand in the absence of Itk. J. Immunol. 193, 673–687.
96. Carty, S. A., Koretzky, G. A., Jordan, M. S. (2012) The role of IL-4 signaling in CD8+ innate-like lymphocyte development. 54th American Society of Hematology Annual Meeting and Exposition (abs.).
97. Carty, S. A., Koretzky, G. A., Jordan, M. S. (2014) Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation. PLoS One 9, e106659.doi:10.1371/journal.pone.0106659
98. So, E. Y., Oh, J., Jang, J. Y., Kim, J. H., Lee, C. E. (2007) Ras/Erk pathway positively regulates Jak1/STAT6 activity and IL-4 gene expression in Jurkat T cells. Mol. Immunol. 44, 3416–3426.
99. Oliver, J. A., Stolberg, V. R., Chensue, S. W., King, P. D. (2012) IL-4 acts as a potent stimulator of IFN-g expression in CD8+ T cells through STAT6-dependent and independent induction of Eomesodermin and T-bet. Cytokine 57, 191–199.
100. Wang, X., Proud, C. G. (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21, 362–369.
101. Zhu, J., Huang, H., Guo, L., Stonehouse, T., Watson, C. J., Hu-Li, J., Paul, W. E. (2000) Transient inhibition of interleukin 4 signaling by T cell receptor ligation. J. Exp. Med. 192, 1125–1134.
102. Au-Yeung, B. B., Katzman, S. D., Fowell, D. J. (2006) Cutting edge: Itkdependent signals required for CD4+ T cells to exert, but not gain, Th2 effector function. J. Immunol. 176, 3895–3899.
103. Kosaka, Y., Felices, M., Berg, L. J. (2006) Itk and Th2 responses: action but no reaction. Trends Immunol. 27, 453–460.
104. O’Shea, J. J., Murray, P. J. (2008) Cytokine signaling modules in inflammatory responses. Immunity 28, 477–487.
105. O’Shea, J. J., Gadina, M., Kanno, Y. (2011) Cytokine signaling: birth of a pathway. J. Immunol. 187, 5475–5478.
106. Stark, G. R., Darnell, Jr., J. E., (2012) The JAK-STAT pathway at twenty. Immunity 36, 503–514.
107. Deshpande, R. V., Goust, J. M., Chakrabarti, A. K., Barbosa, E., Hogan, E. L., Banik, N. L. (1995) Calpain expression in lymphoid cells. Increased mRNA and protein levels after cell activation. J. Biol. Chem. 270, 2497–2505.
108. Noguchi, M., Sarin, A., Aman, M. J., Nakajima, H., Shores, E. W., Henkart, P. A., Leonard, W. J. (1997) Functional cleavage of the common cytokine receptor gamma chain (gammac) by calpain. Proc. Natl. Acad. Sci. USA 94, 11534–11539.
109. Letavernier, E., Dansou, B., Lochner, M., Perez, J., Bellocq, A., Lindenmeyer, M. T., Cohen, C. D., Haymann, J. P., Eberl, G., Baud, L. (2011) Critical role of the calpain/calpastatin balance in acute allograft rejection. Eur. J. Immunol. 41, 473–484.
110. Trager, N., Smith, A., Wallace Iv, G., Azuma, M., Inoue, J., Beeson, C., Haque, A., Banik, N. L. (2014) Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis. J. Neurochem. 130, 268–279.
111. Hong, C., Luckey, M. A., Ligons, D. L., Waickman, A. T., Park, J. Y., Kim, G. Y., Keller, H. R., Etzensperger, R., Tai, X., Lazarevic, V., Feigenbaum, L., Catalfamo, M., Walsh, S. T., Park, J. H. (2014) Activated T cells secrete an alternatively spliced form of common g-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity 40, 910–923.
112. Ip, J. Y., Tong, A., Pan, Q., Topp, J. D., Blencowe, B. J., Lynch, K. W. (2007) Global analysis of alternative splicing during T-cell activation. RNA 13, 563–572.
113. Lynch, K. W., Weiss, A. (2000) A model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates protein kinase C and Ras. Mol. Cell. Biol. 20, 70–80.
114. Wormald, S., Hilton, D. J. (2004) Inhibitors of cytokine signal transduction. J. Biol. Chem. 279, 821–824.
115. Yoshimura, A. (1998) The CIS family: negative regulators of JAK-STAT signaling. Cytokine Growth Factor Rev. 9, 197–204.
116. Yoshimura, A. (1998) The CIS/JAB family: novel negative regulators of JAK signaling pathways. Leukemia 12, 1851–1857.
117. Rawlings, J. S., Rosler, K. M., Harrison, D. A. (2004) The JAK/STAT signaling pathway. J. Cell Sci. 117, 1281–1283.
118. Wu, L., Bijian, K., Shen, S. H. (2009) CD45 recruits adapter protein DOK-1 and negatively regulates JAK-STAT signaling in hematopoietic cells. Mol. Immunol. 46, 2167–2177.
119. Dong, S., Corre, B., Foulon, E., Dufour, E., Veillette, A., Acuto, O., Michel, F. (2006) T Cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J. Exp. Med. 203, 2509–2518.
120. Inoue, A., Yasuda, T., Yamamoto, T., Yamanashi, Y. (2007) Dok-1 is a positive regulator of IL-4 signalling and IgE response. J. Biochem. 142, 257–263.
121. Lee, C. M., Jung, I. D., Noh, K. T., Lee, J. S., Park, J. W., Heo, D. R., Park, J. H., Chang, J. H., Choi, I. W., Kim, J. S., Shin, Y. K., Park, S. J., Han, M. K., Lee, C. G., Cho, W. K., Park, Y. M. (2012) An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma. PLoS ONE 7, e34554.
122. Kosugi, A., Sakakura, J., Yasuda, K., Ogata, M., Hamaoka, T. (2001) Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts. Immunity 14, 669–680.
123. Hebeisen, M., Baitsch, L., Presotto, D., Baumgaertner, P., Romero, P., Michielin, O., Speiser, D. E., Rufer, N. (2013) SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J. Clin. Invest. 123, 1044–1056.
124. Ramanathan, S., Gagnon, J., Leblanc, C., Rottapel, R., Ilangumaran, S. (2006) Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis. J. Immunol. 176, 4029–4041.
125. Banerjee, A., Banks, A. S., Nawijn, M. C., Chen, X. P., Rothman, P. B. (2002) Cutting edge: suppressor of cytokine signaling 3 inhibits activation of NFATp. J. Immunol. 168, 4277–4281.
126. Li, S., Chen, S., Xu, X., Sundstedt, A., Paulsson, K. M., Anderson, P., Karlsson, S., Sjögren, H. O., Wang, P. (2000) Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells. J. Exp. Med. 191, 985–994.
127. Wong, K. A., Kim, R., Christofk, H., Gao, J., Lawson, G., Wu, H. (2004) Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol. Cell. Biol. 24, 5577–5586.
128. Roth, W., Sustmann, C., Kieslinger, M., Gilmozzi, A., Irmer, D., Kremmer, E., Turck, C., Grosschedl, R. (2004) PIASy-deficient mice display modest defects in IFN and Wnt signaling. J. Immunol. 173, 6189–6199.
129. Palvimo, J. J. (2007) PIAS proteins as regulators of small ubiquitinrelated modifier (SUMO) modifications and transcription. Biochem. Soc. Trans. 35, 1405–1408.