Regulation of antigen-experienced T cells: Lessons from the quintessential memory marker CD44

Frontiers in Immunology

Volumn 3, Issue FEB, 2012, Pages

  Baaten, Bas J G ^a   Tinoco, Roberto ^a   Chen, Alex T ^a   Bradley, Linda M ^a  

^a BURNHAM INSTITUTE   (United States)

Author keywords

CD44; Extracellularmatrix; Memory; Migration; Tcell

Indexed keywords

EID: 84874024903     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00023     Document Type: Review

References (107)

1. Alon, R., Kassner, P. D., Carr, M. W., Finger, E. B., Hemler, M. E., and Springer, T. A. (1995). The inte-grin VLA-4 supports tethering and rolling in flow on VCAM-1. J. Cell Biol. 128, 1243-1253.
2. Autero, M., Heiska, L., Ronnstrand, L., Vaheri, A., Gahmberg, C. G., and Carpen, O. (2003). Ezrin is a sub-strate for Lck in T cells. FEBS Lett. 535, 82-86.
3. Baaten, B. J., Li, C. R., Deiro, M. F., Lin, M. M., Linton, P. J., and Bradley, L. M. (2010). CD44 reg-ulates survival and memory devel-opment in Th1 cells. Immunity 32, 104-115.
4. Banerji, S., Wright, A. J., Noble, M., Mahoney, D. J., Campbell, I. D., Day, A. J., and Jackson, D. G. (2007). Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nat. Struct. Mol. Biol. 14, 234-239.
5. Belz, G. T.,Wodarz, D., Diaz, G., Nowak, M. A., and Doherty, P. C. (2002). Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice. J. Virol. 76, 12388-12393.
6. Blass, S. L., Pure, E., and Hunter, C. A. (2001). A role for CD44 in the production of IFN-gamma and immunopathology during infection with Toxoplasma gondii. J. Immunol. 166, 5726-5732.
7. Boise, L. H., Minn, A. J., Noel, P. J., June, C. H., Accavitti, M. A., Lindsten, T., and Thompson, C. B. (1995). CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3, 87-98.
8. Bollyky, P. L., Falk, B. A., Long, S. A., Preisinger, A., Braun, K. R., Wu, R. P., Evanko, S. P., Buckner, J. H., Wight, T. N., and Nepom, G. T. (2009). CD44 costimulation pro-motes FoxP3+ regulatory T cell per-sistence and function via produc-tion of IL-2, IL-10, and TGF-beta. J. Immunol. 183, 2232-2241.
9. Bollyky, P. L., Lord, J. D., Masewicz, S. A., Evanko, S. P., Buckner, J. H., Wight, T. N., and Nepom, G. T. (2007). Cutting edge: high molecu-lar weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells. J. Immunol. 179, 744-747.
10. Bonder, C. S., Clark, S. R., Norman, M. U., Johnson, P., and Kubes, P. (2006). Use of CD44 by CD4+ Th1 and Th2 lymphocytes to roll and adhere. Blood 107, 4798-4806.
11. Bourgeois, C., Rocha, B., and Tanchot, C. (2002). A role for CD40 expres-sion on CD8+ T cells in the genera-tion of CD8+ T cell memory. Science 297, 2060-2063.
12. Bourguignon, L. Y., Peyrollier, K., Xia, W., and Gilad, E. (2008). Hyaluronan-CD44 interaction acti-vates stem cell marker Nanog, Stat-3-mediated MDR1 gene expres-sion, and ankyrin-regulated mul-tidrug efflux in breast and ovar-ian tumor cells. J. Biol. Chem. 283, 17635-17651.
13. Boyman, O., Letourneau, S., Krieg, C., and Sprent, J. (2009). Homeostatic proliferation and survival of naive and memory T cells. Eur. J. Immunol. 39, 2088-2094.
14. Brown, K. L., Birkenhead, D., Lai, J. C., Li, L., Li, R., and Johnson, P. (2005). Regulation of hyaluronan binding by F-actin and colocaliza-tion of CD44 and phosphorylated ezrin/radixin/moesin (ERM) pro-teins in myeloid cells. Exp. Cell Res. 303, 400-414.
15. Camp, R. L., Scheynius, A., Johansson, C., and Pure, E. (1993). CD44 is nec-essary for optimal contact allergic responses but is not required for nor-mal leukocyte extravasation. J. Exp. Med. 178, 497-507.
16. Catron, D. M., Rusch, L. K., Hataye, J., Itano, A. A., and Jenkins, M. K. (2006). CD4+ T cells that enter the draining lymph nodes after anti-gen injection participate in the pri-mary response and become central-memory cells. J. Exp. Med. 203, 1045-1054.
17. Chen, D., Mckallip, R. J., Zeytun, A., Do, Y., Lombard, C., Robertson, J. L., Mak, T. W., Nagarkatti, P. S., and Nagarkatti, M. (2001). CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injec-tion: evidence for involvement of CD44 in activation-induced cell death. J. Immunol. 166, 5889-5897.
18. Cichy, J., Bals, R., Potempa, J., Mani, A., and Pure, E. (2002). Proteinase-mediated release of epithelial cell-associated CD44. Extracellular CD44 complexes with components of cellular matrices. J. Biol. Chem. 277, 44440-44447.
19. DeGrendele, H. C., Kosfiszer, M., Est-ess, P., and Siegelman, M. H. (1997). CD44 activation and associated pri-mary adhesion is inducible via T cell receptor stimulation. J. Immunol. 159, 2549-2553.
20. del Pozo, M. A., Sanchez-Mateos, P., Nieto, M., and Sanchez-Madrid, F. (1995). Chemokines regulate cellu-lar polarization and adhesion recep-tor redistribution during lympho-cyte interaction with endothelium and extracellular matrix. Involve-ment of cAMP signaling pathway. J. Cell Biol. 131, 495-508.
21. Elkington, P. T., O'Kane, C. M., and Friedland, J. S. (2005). The para-dox of matrix metalloproteinases in infectious disease. Clin. Exp. Immunol. 142, 12-20.
22. English, N. M., Lesley, J. F., and Hyman, R. (1998). Site-specific de-N-glycosylation of CD44 can activate hyaluronan binding, and CD44 activation states show distinct threshold densities for hyaluronan binding. Cancer Res. 58, 3736-3742.
23. Fanning, A., Volkov, Y., Freeley, M., Kelleher, D., and Long, A. (2005). CD44 cross-linking induces pro-tein kinase C-regulated migration of human T lymphocytes. Int. Immunol. 17, 449-458.
24. Firan, M., Dhillon, S., Estess, P., and Siegelman, M. H. (2006). Suppres-sor activity and potency among reg-ulatory T cells is discriminated by functionally active CD44. Blood 107, 619-627.
25. Foger, N., Marhaba, R., and Zoller, M. (2000). CD44 supports T cell prolif-eration and apoptosis by apposition of protein kinases. Eur. J. Immunol. 30, 2888-2899.
26. Fooksman,D. R.,Vardhana,S.,Vasiliver-Shamis, G., Liese, J., Blair, D. A., Waite, J., Sacristan, C.,Victora, G. D., Zanin-Zhorov, A., and Dustin, M. L. (2010). Functional anatomy of T cell activation and synapse formation. Annu. Rev. Immunol. 28, 79-105.
27. Forster-Horvath, C., Bocsi, J., Raso, E., Orban, T. I., Olah, E., Timar, J., and Ladanyi, A. (2001). Consti-tutive intracellular expression and activation-induced cell surface up-regulation of CD44v3 in human T lymphocytes. Eur. J. Immunol. 31, 600-608.
28. Gee, K., Kozlowski, M., and Kumar, A. (2003). Tumor necrosis factor-alpha induces functionally active hyaluronan-adhesive CD44 by activating sialidase through p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated human monocytic cells. J. Biol. Chem. 278, 37275-37287.
29. Girish, K. S., and Kemparaju, K. (2007). The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci. 80, 1921-1943.
30. Gonda, A., Gal, I., Szanto, S., Sarraj, B., Glant, T. T., Hunyadi, J., and Mikecz, K. (2005). CD44, but not L-selectin, is critically involved in leu-cocyte migration into the skin in a murine model of allergic dermatitis. Exp. Dermatol. 14, 700-708.
31. Graham, V. A., Marzo, A. L., and Tough, D. F. (2007). A role for CD44 in T cell development and function during direct competition between CD44+ and CD44-cells. Eur. J. Immunol. 37, 925-934.
32. Guan, H., Nagarkatti, P. S., and Nagarkatti, M. (2009). Role of CD44 in the differentiation of Th1 and Th2 cells: CD44-deficiency enhances the development of Th2 effectors in response to sheep RBC and chicken ovalbumin. J. Immunol. 183, 172-180.
33. Guan, H., Nagarkatti, P. S., and Nagarkatti, M. (2011). CD44 recip-rocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. J. Immunol. 186, 6955-6964.
34. Hauptschein, R. S., Sloan, K. E., Torella, C., Moezzifard, R., Giel-Moloney, M., Zehetmeier, C., Unger, C., Ilag, L. L., and Jay, D. G. (2005). Func-tional proteomic screen identifies a modulating role for CD44 in death receptor-mediated apoptosis. Can-cer Res. 65, 1887-1896.
35. He, Q., Lesley, J., Hyman, R., Ishihara, K., and Kincade, P. W. (1992). Mol-ecular isoforms of murine CD44 and evidence that the membrane proximal domain is not critical for hyaluronate recognition. J. Cell Biol. 119, 1711-1719.
36. Hegde, V. L., Singh, N. P., Nagarkatti, P. S., and Nagarkatti, M. (2008). CD44 mobilization in allogeneic dendritic cell-T cell immunological synapse plays a key role in T cell activation. J. Leukoc. Biol. 84, 134-142.
37. Huppa, J. B., and Davis, M. M. (2003). T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973-983.
38. Hur, E. M., Youssef, S., Haws, M. E., Zhang, S. Y., Sobel, R. A., and Steinman, L. (2007). Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat. Immunol. 8, 74-83.
39. Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., Von Herrath, M. G., and Schoenberger, S. P. (2003). CD4+ T cells are required for sec-ondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852-856.
40. Jiang, D., Liang, J., and Noble, P. W. (2011). Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 91, 221-264.
41. Johansen, P., Stamou, P., Tascon, R. E., Lowrie, D. B., and Stockinger, B. (2004). CD4 T cells guarantee optimal competitive fitness of CD8 memory T cells. Eur. J. Immunol. 34, 91-97.
42. Johnson, P., and Ruffell, B. (2009). CD44 and its role in inflamma-tion and inflammatory diseases. Inflamm. Allergy Drug Targets 8, 208-220.
43. Jones, R. G., Elford, A. R., Parsons, M. J., Wu, L., Krawczyk, C. M., Yeh, W. C., Hakem, R., Rottapel, R., Woodgett, J. R., and Ohashi, P. S. (2002). CD28-dependent activa-tion of protein kinase B/Akt blocks Fas-mediated apoptosis by prevent-ing death-inducing signaling com-plex assembly. J. Exp. Med. 196, 335-348.
44. Joshi, N. S., Cui, W., Chandele, A., Lee, H. K.,Urso,D. R.,Hagman,J.,Gapin, L., and Kaech, S. M. (2007). Inflam-mation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281-295.
45. Kaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D., and Ahmed, R. (2003). Selective expres-sion of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191-1198.
46. Kassiotis, G., Garcia, S., Simpson, E., and Stockinger, B. (2002). Impair-ment of immunological memory in the absence of MHC despite survival of memory cells. Nat. Immunol. 3, 244-250.
47. Katoh, S., Matsumoto, N., Kawakita, K., Tominaga, A., Kincade, P. W., and Matsukura, S. (2003). A role for CD44 in an antigen-induced murine model of pulmonary eosinophilia. J. Clin. Invest. 111, 1563-1570.
48. Katoh, S., Miyagi, T., Taniguchi, H., Matsubara, Y., Kadota, J., Tominaga, A., Kincade, P. W., Matsukura, S., and Kohno, S. (1999). Cutting edge: an inducible sialidase regulates the hyaluronic acid binding ability of CD44-bearing human monocytes. J. Immunol. 162, 5058-5061.
49. Kipnis, A., Basaraba, R. J., Turner, J., and Orme, I. M. (2003). Increased neu-trophil influx but no impairment of protective immunity to tuberculosis in mice lacking the CD44 molecule. J. Leukoc. Biol. 74, 992-997.
50. Konig, H., Ponta, H., and Herrlich, P. (1998). Coupling of signal transduc-tion to alternative pre-mRNA splic-ing by a composite splice regulator. EMBO J. 17, 2904-2913.
51. Larkin, J., Renukaradhya, G. J., Sriram, V., Du, W., Gervay-Hague, J., and Brutkiewicz, R. R. (2006). CD44 dif-ferentially activates mouse NK T cells and conventional T cells. J. Immunol. 177, 268-279.
52. Lee, J. L., Wang, M. J., Sudhir, P. R., and Chen,J.Y. (2008). CD44 engagement promotes matrix-derived survival through the CD44-SRC-integrin axis in lipid rafts. Mol. Cell. Biol. 28, 5710-5723.
53. Lefebvre, D. C., Lai, J. C., Maeshima, N., Ford, J. L., Wong, A. S., Cross, J. L., and Johnson, P. (2010). CD44 interacts directly with Lck in a zinc-dependent manner. Mol. Immunol. 47, 1882-1889.
54. Lesley, J., Howes, N., Perschl, A., and Hyman, R. (1994). Hyaluronan binding function of CD44 is tran-siently activated on T cells during an in vivo immune response. J. Exp. Med. 180, 383-387.
55. Ley, K., and Kansas, G. S. (2004). Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat. Rev. Immunol. 4, 325-335.
56. Ley, K., Laudanna, C., Cybulsky, M. I., and Nourshargh, S. (2007). Get-ting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678-689.
57. Li, Y., Jiang, D., Liang, J., Meltzer, E. B., Gray, A., Miura, R., Wogensen, L., Yamaguchi, Y., and Noble, P. W. (2011). Severe lung fibrosis requires an invasive fibroblast phe-notype regulated by hyaluronan and CD44. J. Exp. Med. 208, 1459-1471.
58. Liao, H. X., Levesque, M. C., Patton, K., Bergamo,B.,Jones,D.,Moody,M.A., Telen, M. J., and Haynes, B. F. (1993). Regulation of human CD44H and CD44E isoform binding to hyaluro-nan by phorbol myristate acetate and anti-CD44 monoclonal and poly-clonal antibodies. J. Immunol. 151, 6490-6499.
59. Lin, Y. H., and Yang-Yen, H. F. (2001). The osteopontin-CD44 survival sig-nal involves activation of the phos-phatidylinositol 3-kinase/Akt sig-naling pathway. J. Biol. Chem. 276, 46024-46030.
60. Maeshima, N., Poon, G. F., Dosanjh, M., Felberg, J., Lee, S. S., Cross, J. L., Birkenhead, D., and Johnson, P. (2011). Hyaluronan binding identi-fies the most proliferative activated and memory T cells. Eur. J. Immunol. 41, 1108-1119.
61. Marhaba, R., Freyschmidt-Paul, P., and Zoller, M. (2006). In vivo CD44-CD49d complex formation in autoimmune disease has con-sequencesonTcellactivation and apoptosis resistance. Eur. J. Immunol. 36, 3017-3032.
62. Matloubian, M., Concepcion, R. J., and Ahmed, R. (1994). CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056-8063.
63. Matsumoto, M., Nghiem, M. P., Nozaki, N., Schmits, R., and Penninger, J. M. (1998). Cooperation between CD44 and LFA-1/CD11a adhesion recep-tors in lymphokine-activated killer cell cytotoxicity. J. Immunol. 160, 5781-5789.
64. McDonald, B., Mcavoy, E. F., Lam, F., Gill, V., De La Motte, C., Savani, R. C., and Kubes, P. (2008). Inter-action of CD44 and hyaluronan is the dominant mechanism for neu-trophil sequestration in inflamed liver sinusoids. J. Exp. Med. 205, 915-927.
65. Mielgo, A., Van Driel, M., Bloem, A., Landmann, L., and Gunthert, U. (2006). A novel antiapoptotic mech-anism based on interference of Fas signaling by CD44 variant isoforms. Cell Death Differ. 13, 465-477.
66. Mori, T., Kitano, K., Terawaki, S., Mae-saki, R., Fukami, Y., and Hakoshima, T. (2008). Structural basis for CD44 recognition by ERM proteins. J. Biol. Chem. 283, 29602-29612.
67. Mrass, P., Kinjyo, I., Ng, L. G., Reiner, S. L.,Pure,E.,andWeninger,W. (2008). CD44 mediates successful intersti-tial navigation by killer T cells and enables efficient antitumor immu-nity. Immunity 29, 971-985.
68. Mummert, M. E., Mummert, D., Edel-baum, D., Hui, F., Matsue, H., and Takashima, A. (2002). Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation. J. Immunol. 169, 4322-4331.
69. Nagano, O., and Saya, H. (2004). Mech-anism and biological significance of CD44 cleavage. Cancer Sci. 95, 930-935.
70. Nandi, A., Estess, P., and Siegelman, M. (2004). Bimolecular complex between rolling and firm adhesion receptors required for cell arrest; CD44 association with VLA-4 in T cell extravasation. Immunity 20, 455-465.
71. Ogino, S., Nishida, N., Umemoto, R., Suzuki, M., Takeda, M., Terasawa, H., Kitayama, J., Matsumoto, M., Hayasaka,H.,Miyasaka,M.,and Shi-mada, I. (2010). Two-state confor-mations in the hyaluronan-binding domain regulate CD44 adhesiveness under flow condition. Structure 18, 649-656.
72. Page, T. H., Lali, F. V., and Foxwell, B. M. (1995). Interleukin-7 acti-vates p56lck and p59fyn, two tyro-sine kinases associated with the p90 interleukin-7 receptor in primary human T cells. Eur. J. Immunol. 25, 2956-2960.
73. Page, T. H., Lali, F. V., Groome, N., and Foxwell, B. M. (1997). Association of the common gamma-chain with the human IL-7 receptor is modulated by T cell activation. J. Immunol. 158, 5727-5735.
74. Peng, Y., Chen, J., Shao, W., Wang, F., Dai, H., Cheng, P., Xia, J., Huang, R., Zhu, Q., and Qi, Z. (2011). Xenoreactive CD4(+) memory T cells resist inhibition by anti-CD44 mAb and reject islet grafts via a Th2-dependent pathway. Xenotransplan-tation 18, 252-261.
75. Ponta, H., Sherman, L., and Herrlich, P. (2003). CD44: from adhesion mol-ecules to signaling regulators. Nat. Rev. Mol. Cell Biol. 4, 33-45.
76. Rogers, P. R., Song, J., Gramaglia, I., Killeen, N., and Croft, M. (2001). OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immu-nity 15, 445-455.
77. Rosenman, S. J., Ganji, A. A., Tedder, T. F., and Gallatin, W. M. (1993). Syn-capping of human T lymphocyte adhesion/activation molecules and their redistribution during interac-tion with endothelial cells. J. Leukoc. Biol. 53, 1-10.
78. Roumier, A., Olivo-Marin, J. C., Arpin, M., Michel, F., Martin, M., Mangeat, P., Acuto, O., Dautry-Varsat, A., and Alcover, A. (2001). The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15, 715-728.
79. Rozsnyay, Z. (1999). Signaling complex formation of CD44 with src-related kinases. Immunol. Lett. 68, 101-108
80. Ruffell, B., and Johnson, P. (2008). Hyaluronan induces cell death in activated T cells through CD44. J. Immunol. 181, 7044-7054.
81. Sallusto, F., Geginat, J., and Lanzavec-chia,A. (2004). Central memory and effector memory T cell subsets: func-tion, generation, and maintenance. Annu. Rev. Immunol. 22, 745-763.
82. Sallusto,F.,and Lanzavecchia,A. (2009). Heterogeneity of CD4+ memory T cells: functional modules for tai-lored immunity. Eur. J. Immunol. 39, 2076-2082.
83. Savinov,A. Y., Rozanov, D. V., Golubkov, V. S., Wong, F. S., and Strongin, A. Y. (2005). Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. J. Biol. Chem. 280, 27755-27758.
84. Savinov,A.Y.,and Strongin,A.Y. (2007). Defining the roles of T cell mem-brane proteinase and CD44 in type 1 diabetes. IUBMB Life 59, 6-13.
85. Shedlock, D. J., and Shen, H. (2003). Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337-339.
86. Shinohara, M. L., Jansson, M., Hwang, E. S., Werneck, M. B., Glimcher, L. H., and Cantor, H. (2005). T-bet-dependent expression of osteopon-tin contributes to T cell polariza-tion. Proc. Natl. Acad. Sci. U.S.A. 102, 17101-17106.
87. Shirali, A. C., and Goldstein, D. R. (2008). Activation of the innate immune system by the endoge-nous ligand hyaluronan. Curr. Opin. Organ Transplant 13, 20-25.
88. Siegelman, M. H., Stanescu, D., and Est-ess, P. (2000). The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhe-sion. J. Clin. Invest. 105, 683-691.
89. Sorokin, L. (2010). The impact of the extracellular matrix on inflam-mation. Nat. Rev. Immunol. 10, 712-723.
90. Sun, J. C., and Bevan, M. J. (2003). Defective CD8 T cell memory fol-lowing acute infection without CD4 Tcellhelp.Science 300, 339-342.
91. Taher, T. E., Smit, L., Griffioen, A. W., Schilder-Tol, E. J., Borst, J., and Pals, S. T. (1996). Signaling through CD44 is mediated by tyro-sine kinases. Association with p56lck in T lymphocytes. J. Biol. Chem. 271, 2863-2867.
92. Takeda, M., Ogino, S., Umemoto, R., Sakakura, M., Kajiwara, M., Suga-hara, K. N., Hayasaka, H., Miyasaka, M., Terasawa, H., and Shimada, I. (2006). Ligand-induced structural changes of the CD44 hyaluronan-binding domain revealed by NMR. J. Biol. Chem. 281, 40089-40095.
93. Teder, P., Vandivier, R. W., Jiang, D., Liang, J., Cohn, L., Pure, E., Hen-son, P. M., and Noble, P. W. (2002). Resolution of lung inflammation by CD44. Science 296, 155-158.
94. Thankamony, S. P., and Sackstein, R. (2011). Enforced hematopoietic cell E-and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proc. Natl. Acad. Sci. U.S.A. 108, 2258-2263.
95. Tybulewicz, V. L., and Henderson, R. B. (2009). Rho family GTPases and their regulators in lymphocytes. Nat. Rev. Immunol. 9, 630-644.
96. Varadhachary, A. S., Perdow, S. N., Hu, C., Ramanarayanan, M., and Salgame, P. (1997). Differential ability of T cell subsets to undergo activation-induced cell death. Proc. Natl. Acad. Sci. U.S.A. 94, 5778-5783.
97. Varadhachary, A. S., Peter, M. E., Perdow, S. N., Krammer, P. H., and Salgame, P. (1999). Selective up-regulation of phosphatidylinos-itol 3'-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: a mecha-nism for Th2 resistance from Fas-mediated apoptosis. J. Immunol. 163, 4772-4779.
98. Wang, Q., Teder, P., Jeudd, N. P., Noble, P. W., and Doerschuk, C. M. (2002). CD44 deficiency leads to enhanced neutrophil migration and lung injury in Escherichia coli pneu-monia in mice. Am. J. Pathol. 161, 2219-2228.
99. Weiss, L., Slavin, S., Reich, S., Cohen, P., Shuster, S., Stern, R., Kaganovsky, E., Okon, E., Rubinstein, A. M., and Naor, D. (2000). Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal anti-body. Proc. Natl. Acad. Sci. U.S.A. 97, 285-290.
100. Wittig, B., Schwarzler, C., Fohr, N., Gun-thert, U., and Zoller, M. (1998). Curative treatment of an exper-imentally induced colitis by a CD44 variant V7-specific antibody. J. Immunol. 161, 1069-1073.
101. Wittig, B. M., Johansson, B., Zoller, M., Schwarzler, C., and Gun-thert, U. (2000). Abrogation of experimental colitis correlates with increased apoptosis in mice deficient for CD44 variant exon 7 (CD44v7). J. Exp. Med. 191, 2053-2064.
102. Wolny, P. M., Banerji, S., Gounou, C., Brisson, A. R., Day, A. J., Jackson, D. G., and Richter, R. P. (2010). Analy-sis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan. J. Biol. Chem. 285, 30170-30180.
103. Wong, N. K., Lai, J. C., Maeshima, N., and Johnson, P. (2011). CD44-mediated elongated T cell spreading requires Pyk2 activation by Src family kinases, extracellular calcium, phospholipase C and phosphatidylinositol-3 kinase. Cell. Signal. 23, 812-819.
104. Yago, T., Shao, B., Miner, J. J., Yao, L., Klopocki, A. G., Maeda, K., Cogge-shall, K. M., and Mcever, R. P. (2010). E-selectin engages PSGL-1 and CD44 through a common sig-naling pathway to induce integrin alphaLbeta2-mediated slow leuko-cyte rolling. Blood 116, 485-494.
105. Yu, Q., and Stamenkovic, I. (1999). Localization of matrix metallopro-teinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 13, 35-48.
106. Zhang, X., Brunner, T., Carter, L., Dut-ton, R. W., Rogers, P., Bradley, L., Sato, T., Reed, J. C., Green, D., and Swain, S. L. (1997). Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J. Exp. Med. 185, 1837-1849.
107. Zheng, Z., Katoh, S., He, Q., Oritani, K., Miyake, K., Lesley, J., Hyman, R., Hamik, A., Parkhouse, R. M., Farr, A. G., and Kincade, P. W. (1995). Monoclonal antibodies to CD44 and their influence on hyaluronan recog-nition. J. Cell Biol. 130, 485-495