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Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

ABSTRACT: The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138+Blimp1+ splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.

SUBMITTER: Bagherzadeh Yazdchi S

PROVIDER: S-EPMC6310088 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

Bagherzadeh Yazdchi Sahar S Witalis Mariko M Meli Alexandre P AP Leung Joanne J Li Xin X Panneton Vincent V Chang Jinsam J Li Joanna J Nutt Stephen L SL Johnson Randy L RL Lim Dae-Sik DS Gu Hua H King Irah L IL Suh Woong-Kyung WK

Journal of immunology (Baltimore, Md. : 1950) 20181126 1

The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in y ...[more]

PMID: 30478091

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Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

Publications

Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

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