Cutting Edge: Loss of a4 Integrin Expression Differentially Affects the Homing of Th1 and Th17 Cells

The neutralization of a4 integrin is currently used as treatment in several autoimmune diseases and is thought to prevent the entry of most immune cells in target tissues. In this study, we showed that selective deletion of a4 integrin in T cells did not prevent but delayed the development of experimental autoimmune encephalomyelitis. Whereas both Th1 and Th17 cells infiltrate the CNS of wild-type mice, T cells present in the CNS of mice lacking a4 integrin were mainly enriched in Th17 cells, suggesting that this T cell subset uses other integrins to access the CNS. In contrast, a4 integrin expression is important for Th1 cells to enter the CNS and for the stability of their Th1-associated genetic program. Therefore, our data suggest that anti-a4 integrin Ab treatment may be more efficient in the treatment of Th1-rather than Th17-mediated disease. E xperimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) characterized by multifocal areas of leukocyte infiltration, demyelination, and axonal damage (1). Two subsets of myelin-specific CD4 + T cells have been implicated in the pathoge-nicity of MS and EAE: Th1 cells and Th17 cells (2–5). Trafficking of autoreactive CD4 + T cells from the systemic compartment into the CNS are crucial early events in the development of MS and EAE lesions and involve specific adhesion molecules (1). a4 (Itga4) b1 (Itgb1) integrin or VLA-4 has been proposed as the major adhesion molecule allowing the entry of T cells in the CNS. Treatment of mice with an anti-a4 integrin Ab has been shown to dramatically reduce leukocyte adhesion and prevent the development of EAE in most animal models (6, 7), except in C57BL/6 mice MOG-induced EAE, in which it has limited effect on clinical disease (8, 9). Based on these observations, a humanized anti-Itga 4 mAb was generated to treat patients with MS. Although clinical trials showed a drastic reduction in MS relapse rate, a significant number of patients developed a life-threatening condition called lethal progressive multifocal leukoencephal-opathy (10). Therefore, it is important to determine the effect of Itga 4 blockade on the migration of different subsets of immune cells in the CNS. In this article, we show that mice with selective deletion of Itga 4 on CD4 + T cells are still susceptible to EAE development. Whereas the number of CNS-infiltrating Th1 cells was significantly decreased, the number of CNS-infiltrating Th17 cells was not impaired in these …