Abstract
Abstract Wiskott-Aldrich syndrome protein (WASP)-deficient T cells exhibit defects in IL-2 production that are widely believed to stem from primary defects in actin remodeling and immune synapse formation. Surprisingly, however, we find that WASP-deficient T cells responding to Ag-specific APCs polymerize actin and organize talin and PKCθ normally, forming an immune synapse that is stable for at least 3 h. At low doses of peptide, WASP-deficient T cells show less efficient talin and PKCθ polarization. Thus, although WASP may facilitate immune synapse formation at low peptide concentrations, WASP is not required for this process. Defects in IL-2 production are observed even under conditions in which immune synapse formation proceeds normally, suggesting that the role of WASP in regulating IL-2 production is independent of its role in immune synapse formation.
References
34
Referenced
99
-
Dustin, M. L., J. A. Cooper. 2000. The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nat. Immunol. 1:23.
(
10.1038/76877
) -
Bromley, S. K., W. R. Burack, K. G. Johnson, K. Somersalo, T. N. Sims, C. Sumen, M. M. Davis, A. S. Shaw, P. M. Allen, M. L. Dustin. 2001. The immunological synapse. Annu. Rev. Immunol. 19:375.
(
10.1146/annurev.immunol.19.1.375
) -
Monks, C. R., B. A. Freiberg, H. Kupfer, N. Sciaky, A. Kupfer. 1998. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82.
(
10.1038/25764
) -
Snapper, S. B., F. S. Rosen. 1999. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu. Rev. Immunol. 17:905.
(
10.1146/annurev.immunol.17.1.905
) -
Zhang, J., A. Shehabeldin, L. A. da Cruz, J. Butler, A. K. Somani, M. McGavin, I. Kozieradzki, A. O. dos Santos, A. Nagy, S. Grinstein, J. M. Penninger, K. A. Siminovitch. 1999. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190:1329.
(
10.1084/jem.190.9.1329
) -
Krawczyk, C., J. M. Penninger. 2001. Molecular controls of antigen receptor clustering and autoimmunity. Trends Cell Biol. 11:212.
(
10.1016/S0962-8924(01)01981-X
) - Ochs, H. D.. 1998. The Wiskott-Aldrich syndrome. Semin. Hematol. 35:332.
-
Snapper, S. B., F. S. Rosen, E. Mizoguchi, P. Cohen, W. Khan, C. H. Liu, T. L. Hagemann, S. P. Kwan, R. Ferrini, L. Davidson, A. K. Bhan, F. W. Alt. 1998. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9:81.
(
10.1016/S1074-7613(00)80590-7
) -
Stowers, L., D. Yelon, L. J. Berg, J. Chant. 1995. Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc. Natl. Acad. Sci. USA 92:5027.
(
10.1073/pnas.92.11.5027
) -
Dupre, L., A. Aiuti, S. Trifari, S. Martino, P. Saracco, C. Bordignon, M. G. Roncarolo. 2002. Wiskott-Aldrich syndrome protein regulates lipid raft dynamics during immunological synapse formation. Immunity 17:157.
(
10.1016/S1074-7613(02)00360-6
) -
Higgs, H. N., T. D. Pollard. 2001. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Annu. Rev. Biochem. 70:649.
(
10.1146/annurev.biochem.70.1.649
) -
Cannon, J. L., C. M. Labno, G. Bosco, A. Seth, M. H. McGavin, K. A. Siminovitch, M. K. Rosen, J. K. Burkhardt. 2001. Wasp recruitment to the T cell: APC contact site occurs independently of cdc42 activation. Immunity 15:249.
(
10.1016/S1074-7613(01)00178-9
) -
Zeng, R., J. L. Cannon, R. T. Abraham, M. Way, D. D. Billadeau, J. Bubeck-Wardenberg, J. K. Burkhardt. 2003. SLP-76 coordinates Nck-dependent WASP recruitment with Vav-1/Cdc42-dependent WASP activation at the T cell-APC contact site. J. Immunol. 171:1360.
(
10.4049/jimmunol.171.3.1360
) -
Labno, C. M., C. M. Lewis, D. You, D. W. Leung, A. Takesono, N. Kamberos, A. Seth, L. D. Finkelstein, M. K. Rosen, P. L. Schwartzberg, J. K. Burkhardt. 2003. Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Curr. Biol. 13:1619.
(
10.1016/j.cub.2003.08.005
) -
Badour, K., J. Zhang, F. Shi, Y. Leng, M. Collins, K. A. Siminovitch. 2004. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J. Exp. Med. 199:99.
(
10.1084/jem.20030976
) -
Torres, E., M. K. Rosen. 2003. Contingent phosphorylation/dephosphorylation provides mechanisms of signal integration and molecular memory in WASP. Mol. Cell. 11:1215.
(
10.1016/S1097-2765(03)00139-4
) -
Badour, K., J. Zhang, F. Shi, M. K. McGavin, V. Rampersad, L. A. Hardy, D. Field, K. A. Siminovitch. 2003. The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18:141.
(
10.1016/S1074-7613(02)00516-2
) -
Ramesh, N., I. M. Anton, J. H. Hartwig, R. S. Geha. 1997. WIP, a protein associated with Wiskott-Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc. Natl. Acad. Sci. USA 94:14671.
(
10.1073/pnas.94.26.14671
) -
Volkman, B. F., K. E. Prehoda, J. A. Scott, F. C. Peterson, W. A. Lim. 2002. Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich syndrome. Cell 111:565.
(
10.1016/S0092-8674(02)01076-0
) -
Sasahara, Y., R. Rachid, M. J. Byrne, M. A. de la Fuente, R. T. Abraham, N. Ramesh, R. S. Geha. 2002. Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol. Cell 10:1269.
(
10.1016/S1097-2765(02)00728-1
) -
Anton, I. M., M. A. de la Fuente, T. N. Sims, S. Freeman, N. Ramesh, J. H. Hartwig, M. L. Dustin, R. S. Geha. 2002. WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. Immunity 16:193.
(
10.1016/S1074-7613(02)00268-6
) -
Krawczyk, C., A. Oliveira-dos-Santos, T. Sasaki, E. Griffiths, P. S. Ohashi, S. Snapper, F. Alt, J. M. Penninger. 2002. Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen-presenting cells. Immunity 16:331.
(
10.1016/S1074-7613(02)00291-1
) -
Cannon, J. L., J. K. Burkhardt. 2002. The regulation of actin remodeling during T-cell-APC conjugate formation. Immunol. Rev. 186:90.
(
10.1034/j.1600-065X.2002.18609.x
) -
Allenspach, E. J., P. Cullinan, J. Tong, Q. Tang, A. G. Tesciuba, J. L. Cannon, S. M. Takahashi, R. Morgan, J. K. Burkhardt, A. I. Sperling. 2001. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 15:739.
(
10.1016/S1074-7613(01)00224-2
) -
Sedwick, C. E., M. M. Morgan, L. Jusino, J. L. Cannon, J. Miller, J. K. Burkhardt. 1999. TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization. J. Immunol. 162:1367.
(
10.4049/jimmunol.162.3.1367
) -
Schwartz, R. H., B. S. Fox, E. Fraga, C. Chen, B. Singh. 1985. The T lymphocyte response to cytochrome c. V. Determination of the minimal peptide size required for stimulation of T cell clones and assessment of the contribution of each residue beyond this size to antigenic potency. J. Immunol. 135:2598.
(
10.4049/jimmunol.135.4.2598
) -
Kaye, J., S. M. Hedrick. 1988. Analysis of specificity for antigen, Mls, and allogenic MHC by transfer of T-cell receptor α- and β-chain genes. Nature 336:580.
(
10.1038/336580a0
) -
Lee, K. H., A. D. Holdorf, M. L. Dustin, A. C. Chan, P. M. Allen, A. S. Shaw. 2002. T cell receptor signaling precedes immunological synapse formation. Science 295:1539.
(
10.1126/science.1067710
) -
Wang, R., A. Nelson, K. Kimachi, H. M. Grey, A. G. Farr. 1998. The role of peptides in thymic positive selection of class II major histocompatibility complex-restricted T cells. Proc. Natl. Acad. Sci. USA 95:3804.
(
10.1073/pnas.95.7.3804
) -
Sims, T. N., M. L. Dustin. 2002. The immunological synapse: integrins take the stage. Immunol. Rev. 186:100.
(
10.1034/j.1600-065X.2002.18610.x
) -
Lee, K. H., A. R. Dinner, C. Tu, G. Campi, S. Raychaudhuri, R. Varma, T. N. Sims, W. R. Burak, H. Wu, J. Wang, et al 2003. The immunological synapse balances T cell receptor signaling and degradation. Science 302:1218.
(
10.1126/science.1086507
) -
Bubeck-Wardenburg, J., R. Pappu, J. Y. Bu, B. Mayer, J. Chernoff, D. Straus, A. C. Chan. 1998. Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9:607.
(
10.1016/S1074-7613(00)80658-5
) -
Silvin, C., B. Belisle, A. Abo. 2001. A role for Wiskott-Aldrich syndrome protein in T-cell receptor-mediated transcriptional activation independent of actin polymerization. J. Biol. Chem. 276:21450.
(
10.1074/jbc.M010729200
) -
Sato, M., N. M. Tsuji, H. Gotoh, K. Yamashita, K. Hashimoto, N. Tadotsu, H. Yamanaka, K. Sekikawa, Y. Hashimoto. 2001. Overexpression of the Wiskott-Aldrich syndrome protein N-terminal domain in transgenic mice inhibits T cell proliferative responses via TCR signaling without affecting cytoskeletal rearrangements. J. Immunol. 167:4701.
(
10.4049/jimmunol.167.8.4701
)
Dates
Type | When |
---|---|
Created | 11 years, 4 months ago (April 22, 2014, 11:38 p.m.) |
Deposited | 8 months ago (Jan. 2, 2025, 12:25 p.m.) |
Indexed | 1 week, 3 days ago (Aug. 27, 2025, 11:53 a.m.) |
Issued | 21 years, 1 month ago (Aug. 1, 2004) |
Published | 21 years, 1 month ago (Aug. 1, 2004) |
Published Print | 21 years, 1 month ago (Aug. 1, 2004) |
@article{Cannon_2004, title={Differential Roles for Wiskott-Aldrich Syndrome Protein in Immune Synapse Formation and IL-2 Production}, volume={173}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.173.3.1658}, DOI={10.4049/jimmunol.173.3.1658}, number={3}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Cannon, Judy L. and Burkhardt, Janis K.}, year={2004}, month=aug, pages={1658–1662} }