Cbl-b-deficient mice demonstrate alterations in T cell trafficking but retain sensitivity to the Multiple Sclerosis therapeutic agent FTY720 (THER7P.957)

The variable response to treatment options in multiple sclerosis (MS) suggests the need for genetic-based personalized therapeutic approaches. CBLB gene polymorphisms have been identified in MS, and altered T cell function and aberrant responses to interferon-β in MS patients with a CBLB mutation have been recently reported. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b -/- ) mice show many T cell abnormalities also described in MS patients. This suggests that Cbl-b -/- mice may provide a novel approach for analyzing treatment options in patients with MS-associated CBLB mutations. We now report that Cbl-b -/- CD4 + T cells show significant trafficking-related abnormalities: decreased lymph node accumulation after adoptive transfer into RAG-1 -/- mice; increased sphingosine-1-phosphate receptor 1 (S1P 1 ) expression; and decreased CD69 expression compared to wild-type cells. These data imply that CBLB mutations may compromise the therapeutic efficacy of FTY720, an MS-approved drug that modulates S1P 1 expression. Despite altered Cbl-b -/- T cell trafficking, we observed robust inhibition of EAE by FTY720 in Cbl-b -/- mice. These results not only document a novel role for Cbl-b in T cell trafficking but also indicate that FTY270 may be effective in EAE/MS through mechanisms other than T cell lymph node trapping. Moreover, our findings suggest that FTY720 treatment is still an appropriate choice in patients with MS-associated CBLB mutations.