Molecular basis for T cell response induced by altered peptide ligand of type II collagen

Jeoung Eun Park, David Cullins, Lillian Zalduondo, Stacey L. Barnett, Ae-Kyung Yi, Sandra Kleinau, John Stuart, Andrew Kang, Linda Myers

Research output: Contribution to journalArticle

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Abstract

Mounting evidence from animal models has demonstrated that alterations in peptide-MHC interactions with the T cell receptor (TCR) can lead to dramatically different T cell outcomes. We have developed an altered peptide ligand of type II collagen, referred to as A9, which differentially regulates TCR signaling in murine T cells leading to suppression of arthritis in the experimental model of collagen-induced arthritis. This study delineates the T cell signaling pathway used by T cells stimulated by the A9·I-Aq complex. We have found that T cells activated by A9 bypass the requirement for Zap-70 and CD3-ζand signal via FcRγ and Syk. Using collagen-specific T cell hybridomas engineered to overexpress either Syk, Zap-70, TCR-FcR γ, or CD3-ζ, we demonstrate that A9·I-Aq preferentially activates FcRγ/Syk but not CD3-ζ/Zap-70. Moreover, a genetic absence of Syk or FcRγ significantly reduces the altered peptide ligand induction of the nuclear factor GATA3. By dissecting the molecular mechanism of A9-induced T cell signaling we have defined a new alternate pathway that is dependent upon FcRγand Syk to secrete immunoregulatory cytokines. Given the interest in using Syk inhibitors to treat patients with rheumatoid arthritis, understanding this pathway may be critical for the proper application of this therapy.

Original languageEnglish (US)
Pages (from-to)19765-19774
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number23
DOIs
StatePublished - Jun 1 2012

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T-cells
Collagen Type II
Ligands
T-Lymphocytes
Peptides
T-Cell Antigen Receptor
Cell signaling
Collagen
Experimental Arthritis
Hybridomas
Mountings
Arthritis
Rheumatoid Arthritis
Animals
Theoretical Models
Animal Models
Cytokines

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Molecular basis for T cell response induced by altered peptide ligand of type II collagen. / Park, Jeoung Eun; Cullins, David; Zalduondo, Lillian; Barnett, Stacey L.; Yi, Ae-Kyung; Kleinau, Sandra; Stuart, John; Kang, Andrew; Myers, Linda.

In: Journal of Biological Chemistry, Vol. 287, No. 23, 01.06.2012, p. 19765-19774.

Research output: Contribution to journalArticle

Park, Jeoung Eun ; Cullins, David ; Zalduondo, Lillian ; Barnett, Stacey L. ; Yi, Ae-Kyung ; Kleinau, Sandra ; Stuart, John ; Kang, Andrew ; Myers, Linda. / Molecular basis for T cell response induced by altered peptide ligand of type II collagen. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 23. pp. 19765-19774.
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