Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4+ T cells

Kaminski, Sandra; Hermann-Kleiter, Natascha; Meisel, Marlies; Thuille, Niκolaus; Cronin, Shane J. F.; Hara, Hiromitsu; Fresser, Friedrich; Penninger, Josef; Baier, Gottfried

doi:10.1016/j.jaut.2011.05.018

Cited by 35 publications

(28 citation statements)

References 66 publications

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“…Unexpectedly, considering the decreased EAE symptoms upon primary immunization with the MOG peptide, Coro1a-deficient mice not only overcome the defect observed during initial induction, but also demonstrate hypersusceptibility upon the reinduction of EAE (14). The authors explain this phenotype by defective SMAD3-meditated TGF␤ receptor signaling, resulting in enhanced interferon-␥ and interleukin-17 production when T cells lack Coro1a.…”

Section: Discussionmentioning

confidence: 98%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Deletion Of Coro1a In T Cells Protects From the Development mentioning

confidence: 99%

“…Common to all four Coro1a-deficient mice strains, which were generated in different laboratories, are strongly reduced peripheral T cell counts (11)(12)(13)(14). Naive T cells are especially impaired, whereas effector/memory and regulatory T cells (Treg) are far less affected by the deletion of Coro1a.…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Siegmund

Klepsch

Hermann-Kleiter

et al. 2016

Journal of Biological Chemistry

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Coronins are evolutionarily conserved proteins that were originally identified as modulators of actin-dependent processes. Studies analyzing complete Coronin 1a knock-out mice have shown that this molecule is an important regulator of naive T cell homeostasis and it has been linked to immune deficiencies as well as autoimmune disorders. Nevertheless, because Coronin 1A is strongly expressed in all leukocyte subsets, it is not conclusive whether or not this phenotype is attributed to a T cell-intrinsic function of Coronin 1A. To address this research question, we have generated a T cell-specific Coronin 1a knockout mouse (Coro1a fl/fl ؋ Cd4[Cre]). Deletion of Coronin 1A specifically in T cells led to a strong reduction in T cell number and a shift toward the effector/memory phenotype in peripheral lymphoid organs when compared with Cd4[Cre] mice expressing wild-type Coronin 1A. In contrast to peripheral lymphoid tissue, thymocyte number and subsets were not affected by the deletion of Coronin 1a. Furthermore, T cell-specific Coronin 1a knock-out mice were largely resistant to the induction of autoimmunity when tested in the myelin oligoglycoprotein-induced EAE mouse model of multiple sclerosis. Thus, the phenotype of T cell-specific Coronin 1a deletion resembles the phenotype observed with conventional (whole body) Coronin 1a knock-out mice. In summary, our findings provide formal proof of the predominant T cell-intrinsic role of Coronin 1A.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Deletion Of Coro1a In T Cells Protects From the Development mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Siegmund

Klepsch

Hermann-Kleiter

et al. 2016

Journal of Biological Chemistry

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Compound Heterozygous CORO1A Mutations in Siblings with a Mucocutaneous-Immunodeficiency Syndrome of Epidermodysplasia Verruciformis-HPV, Molluscum Contagiosum and Granulomatous Tuberculoid Leprosy

et al. 2014

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Purpose Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T-B+NK+severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred. Methods We captured a 10-year analysis of the immuneclinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings. Results We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA+ (naïve) T and memory B cells, low NK cells and abnormally increased doublenegative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations. Conclusion We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal naïve CD4 and DN T-cells and newfound characteristics of a late/hypomorphiclike SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.

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Coronin-1A: Immune Deficiency in Humans and Mice

Punwani

Pelz²,

et al. 2015

J Clin Immunol

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Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4+ T cells

Cited by 35 publications

References 66 publications

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

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

Compound Heterozygous CORO1A Mutations in Siblings with a Mucocutaneous-Immunodeficiency Syndrome of Epidermodysplasia Verruciformis-HPV, Molluscum Contagiosum and Granulomatous Tuberculoid Leprosy

Coronin-1A: Immune Deficiency in Humans and Mice

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