| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
*
The Ben May Institute for Cancer Research and
Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637;
Department of Internal Medicine, Division of Nephrology, Mayo Clinic and Foundation, Rochester, MN 55905;
§
Department of Biochemistry, University of Illinois, Urbana, IL 61801;
¶
Genetics Institute, Cambridge, MA 02140; and
||
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
CTLA-4 (CD152) engagement can down-regulate T cell activation and
promote the induction of immune tolerance. However, the strategy of
attenuating T cell activation by engaging CTLA-4 has been limited by
sharing of its natural ligands with the costimulatory protein CD28. In
the present study, a CTLA-4-specific single-chain Ab (scFv) was
developed and expressed on the cell surface to promote selective
engagement of this regulatory molecule. Transfectants expressing
anti-CTLA-4 scFv at their surface bound soluble CTLA-4 but not
soluble CD28. Coexpression of anti-CTLA-4 scFv with anti-CD3
and anti-CD28 scFvs on artificial APCs reduced the proliferation
and IL-2 production by resting and preactivated bulk T cells as well as
CD4+ and CD8+ T cell subsets. Importantly,
expression of anti-CTLA-4 scFv on the same cell surface as the TCR
ligand was essential for the inhibitory effects of CTLA-4-specific
ligation. CTLA-4-mediated inhibition of tyrosine phosphorylation of
components of the proximal TCR signaling apparatus was similarly
dependent on coexpression of TCR and CTLA-4 ligands on the same
surface. These findings support a predominant role for CTLA-4 function
in the modification of the proximal TCR signal. Using T cells from
DO11.10 and 2C TCR transgenic mice, negative regulatory effects of
selective CTLA-4 ligation were also demonstrated during the stimulation
of Ag-specific CD4+ and CD8+ T cells by
MHC/peptide complexes. Together these studies demonstrate that
selective ligation of CTLA-4 using a membrane-bound scFv results in
attenuated T cell responses only when coengaged with the TCR during T
cell/APC interaction and define an approach to harnessing the
immunomodulatory potential of CTLA-4-specific
ligation.
This article has been cited by other articles:
|
|
 |
|
  S. Caserta, P. Alessi, J. Guarnerio, V. Basso, and A. Mondino Synthetic CD4+ T Cell-Targeted Antigen-Presenting Cells Elicit Protective Antitumor Responses Cancer Res., April 15, 2008; 68(8): 3010 - 3018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. A. Coenen, H. J. P. M. Koenen, E. van Rijssen, L. Boon, I. Joosten, and L. B. Hilbrands CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade J. Immunol., May 1, 2006; 176(9): 5240 - 5246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chikuma, A. K. Abbas, and J. A. Bluestone B7-Independent Inhibition of T Cells by CTLA-4 J. Immunol., July 1, 2005; 175(1): 177 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vasu, B. S. Prabhakar, and M. J. Holterman Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity J. Immunol., August 15, 2004; 173(4): 2866 - 2876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Madrenas, L. A. Chau, W. A. Teft, P. W. Wu, J. Jussif, M. Kasaian, B. M. Carreno, and V. Ling Conversion of CTLA-4 from Inhibitor to Activator of T Cells with a Bispecific Tandem Single-Chain Fv Ligand J. Immunol., May 15, 2004; 172(10): 5948 - 5956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Prud'homme Altering immune tolerance therapeutically: the power of negative thinking J. Leukoc. Biol., April 1, 2004; 75(4): 586 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ariyan, P. Salvalaggio, S. Fecteau, S. Deng, L. Rogozinski, D. Mandelbrot, A. Sharpe, M. H. Sayegh, G. P. Basadonna, and D. M. Rothstein Cutting Edge: Transplantation Tolerance through Enhanced CTLA-4 Expression J. Immunol., December 1, 2003; 171(11): 5673 - 5677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Agadjanyan, M. A. Chattergoon, M. J. Holterman, B. Monzavi-Karbassi, J. J. Kim, T. Dentchev, D. Wilson, V. Ayyavoo, L. J. Montaner, T. Kieber-Emmons, et al. Costimulatory Molecule Immune Enhancement in a Plasmid Vaccine Model Is Regulated in Part Through the Ig Constant-Like Domain of CD80/86 J. Immunol., October 15, 2003; 171(8): 4311 - 4319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Vasu, S. R. Gorla, B. S. Prabhakar, and M. J. Holterman Targeted engagement of CTLA-4 prevents autoimmune thyroiditis Int. Immunol., May 1, 2003; 15(5): 641 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Hogan, M. D. Griffin, S. Rossetti, V. E. Torres, C. J. Ward, and P. C. Harris PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression Hum. Mol. Genet., March 15, 2003; 12(6): 685 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bennett, D. Luxenberg, V. Ling, I-M. Wang, K. Marquette, D. Lowe, N. Khan, G. Veldman, K. A. Jacobs, V. E. Valge-Archer, et al. Program Death-1 Engagement Upon TCR Activation Has Distinct Effects on Costimulation and Cytokine-Driven Proliferation: Attenuation of ICOS, IL-4, and IL-21, But Not CD28, IL-7, and IL-15 Responses J. Immunol., January 15, 2003; 170(2): 711 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mukherjee, P. K. Maiti, and D. Nandi Role of CD80, CD86, and CTLA4 on mouse CD4+ T lymphocytes in enhancing cell-cycle progression and survival after activation with PMA and ionomycin J. Leukoc. Biol., November 1, 2002; 72(5): 921 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Hwang, W. B. Sweatt, I. E. Brown, C. Blank, T. F. Gajewski, J. A. Bluestone, and M.-L. Alegre Cutting Edge: Targeted Ligation of CTLA-4 In Vivo by Membrane-Bound Anti-CTLA-4 Antibody Prevents Rejection of Allogeneic Cells J. Immunol., July 15, 2002; 169(2): 633 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mirshahidi, C.-T. Huang, and S. Sadegh-Nasseri Anergy in Peripheral Memory CD4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor J. Exp. Med., September 10, 2001; 194(6): 719 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Riley, P. J. Blair, J. T. Musser, R. Abe, K. Tezuka, T. Tsuji, and C. H. June ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement J. Immunol., April 15, 2001; 166(8): 4943 - 4948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Sullivan, J. J. Letterio, A. van Elsas, M. Mamura, J. van Amelsfort, S. Sharpe, B. Metzler, C. A. Chambers, and J. P. Allison Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation PNAS, February 15, 2001; (2001) 51632398. [Abstract] [Full Text]
|
|
|
|
|
|
T. J. Sullivan, J. J. Letterio, A. van Elsas, M. Mamura, J. van Amelsfort, S. Sharpe, B. Metzler, C. A. Chambers, and J. P. Allison Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation PNAS, February 27, 2001; 98(5): 2587 - 2592. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
