期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 1, 页码 69-78出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1701407
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资金
- Canadian Institutes of Health Research [84544, 298580]
- Fonds de Recherche du Quebec-Sante
- National Creative Research Initiative Program [20120001228]
- Science Research Center Program [NRF-2016R1A5A1010764]
- National Institutes of Health [R01 DK102611]
- National Health and Medical Research Council of Australia [1054925, 1058238]
- Victorian State Government Operational Infrastructure Support Scheme
- National Health and Medical Research Council of Australia [1058238] Funding Source: NHMRC
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.
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