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

Autor:	Bagherzadeh Yazdchi S; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada., Witalis M; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Molecular Biology Program, University of Montreal, Montreal, Quebec H3C 3J7, Canada., Meli AP; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada., Leung J; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada., Li X; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada., Panneton V; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Department of Microbiology, Infectiology, and Immunology, University of Montreal, Montreal, Quebec H3T 1J4, Canada., Chang J; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Molecular Biology Program, University of Montreal, Montreal, Quebec H3C 3J7, Canada., Li J; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada., Nutt SL; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia., Johnson RL; Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030; and., Lim DS; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea., Gu H; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada., King IL; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada., Suh WK; Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada; woong-kyung.suh@ircm.qc.ca.; Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.; Molecular Biology Program, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Jan 01; Vol. 202 (1), pp. 69-78. Date of Electronic Publication: 2018 Nov 26.
DOI:	10.4049/jimmunol.1701407
Abstrakt:	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. (Copyright © 2018 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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