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Expression of the Tyrosine Phosphatase Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 Determines T Cell Activation Threshold and Severity of Experimental Autoimmune Encephalomyelitis¹

Caishu Deng^*, Alfredo Minguela^,, Rehana Z. Hussain^*, Amy E. Lovett-Racke^*, Caius Radu^,, E. Sally Ward^, and Michael K. Racke^2,*,

^* Department of Neurology, Center for Immunology, and Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390

Experimental autoimmune encephalomyelitis (EAE) is a CD4 Th1-mediated inflammatory demyelinating disorder of the CNS and a well-established animal model for multiple sclerosis. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAE pathogenesis, we immunized B10.PL mice heterozygous for deletion of the SHP-1 gene (me^v+/-) and B10.PL wild-type mice with the immunodominant epitope of myelin basic protein (MBP Ac1-11). T cell proliferation and IFN- production were significantly increased in me^v+/- mice after immunization with MBP Ac1-11. The frequency of MBP Ac1-11-specific CD4 T cells, analyzed by staining with fluorescently labeled tetramers (MBP1-11[4Y]: I-A^u complexes), was increased in the draining lymph node cells of me^v+/- mice compared with wild-type mice. In addition, me^v+/- mice developed a more severe course of EAE with epitope spreading to proteolipid protein peptide 43-64. Finally, expansion of MBP Ac1-11-specific T cells in response to Ag was enhanced in me^v+/- T cells, particularly at lower Ag concentrations. These data demonstrate that the level of SHP-1 plays an important role in regulating the activation threshold of autoreactive T cells.

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