Coronin 1-Mediated Naive T Cell Survival Is Essential for the Development of Autoimmune Encephalomyelitis

Abstract

Autoimmune encephalomyelitis is a disease of the CNS that can develop when an initial peripheral inflammatory stimulus is followed by infiltration and reactivation of T lymphocytes in the CNS. We report a crucial role for coronin 1, which is essential for maintenance of the naive T cell pool, for the development of murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In the absence of coronin 1, immunization with myelin oligoglycoprotein (MOG35–55) peptide largely failed to induce EAE symptoms, despite normal mobilization of leukocyte subsets in the blood, as well as effector cytokine expression comparable with wild-type T cells on polyclonal stimulation. Susceptibility of coronin 1-deficient mice to EAE induction was restored by transfer of wild-type CD4+ T cells, suggesting that the observed resistance of coronin 1-deficient mice to EAE development is T cell intrinsic. Importantly, although coronin 1-deficient regulatory T cells (Tregs) showed a suppressor activity comparable with wild-type Tregs, Treg depletion failed to restore EAE development in coronin 1-deficient animals. These results suggest a hitherto unrecognized role of naive T cells in the development of autoimmune encephalomyelitis and reveal coronin 1 as a crucial modulator of EAE induction.

Proof of Principle for a T Lymphocyte Intrinsic Function of Coronin 1A

“…On one hand, the transfer of T cells baring the point mutation described above was sufficient to reduce lupus-like diseases (15). On the other hand, the transfer of wildtype CD4 ϩ T cells before immunization did restore the susceptibility of Coro1a-deficient mice to EAE induction (17). The later experimental approach suggests that Coro1a-deficient APCs are fully capable of priming T cells and promoting effector T cell differentiation as long as those T cells express Coro1A.…”

“…This point mutation introduces a stop codon in the middle of the protein, leading to a truncated version of Coro1A, which fails to localize to the plasma membrane. Furthermore, conventional Coro1a-deficient mice, generated independently in distinct laboratories, were protected against the development of severe signs of EAE induced by immunization with the MOG peptide (14,17). This phenotype has been attributed to alterations of intrinsic T cell function, namely impaired migration, cell activation, and survival.…”

“…The most striking phenotype of conventional Coro1a knock-out mice was their resistance to EAE induction using the MOG(35-55) peptide-based protocol (14,17). Given the similar phenotype of mice harboring either T cell-specific or germline deletion of Coro1a, we expected that deletion of Coro1a in T cells would also confer protection in this model of autoimmunity.…”

“…A nonsense mutation of Coro1a has been identified to suppress disease development in a mouse model of lupus erythematosus (15). Furthermore, Coro1a-deficient mice develop no or only mild symptoms of autoimmunity when immunized with the myelin oligoglycoprotein (MOG) peptide to induce experimental autoimmune encephalomyelitis (EAE), a common murine model of multiple sclerosis (14,17).…”

Constitutive Turnover of Phosphorylation at Thr-412 of Human p57/Coronin-1 Regulates the Interaction with Actin

“…In mice deficient in the p57/coronin-1 gene, differentiation and chemokine-mediated trafficking of T cells were severely impaired (22,24,25). It was further demonstrated that the developments of experimental autoimmune encephalomyelitis (26,27) and lupus-like autoimmune disease (28) were suppressed in mice with genetic defects of p57/coronin-1. These studies suggested the potential relevance of p57/coronin-1 to allergic and autoimmune diseases.…”