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CRTC2 Regulates Plasma Cell Metaboli...

Hong, Jason S.

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CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses./
作者:	Hong, Jason S.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	123 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27738867
ISBN:	9798645490317

CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses.
Hong, Jason S.

CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 123 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2020.

This item must not be sold to any third party vendors.

The humoral immune response is mediated by antigen activated B cells that have terminally differentiated into antibody secreting cells (ASCs). The ASC pool is composed of short-lived plasma cells (SLPCs) and long-lived plasma cells (LLPCs) that secrete antigen-specific antibodies to clear an infection and maintain long-term protective antibody titers to prevent subsequent reinfections. SLPCs have generally been viewed to be formed from T cell-independent immune responses and localized in the spleen. LLPCs have been viewed to be formed from T cell-dependent immune responses and localized in the bone marrow. However, regardless of the type of stimulating antigen, ASCs of varying lifespans, both SLPCs and LLPCs are found in the spleen and bone marrow. Currently, it remains unclear as to what factors and pathways regulate PC longevity.Our laboratory previously identified the CREB coactivator CRTC2 as a regulator of ASC differentiation. DNA double strand breaks associated with class switch recombination activates a signaling pathway in human germinal center (GC) B cells that results in the phosphorylation and inactivation of CRTC2. Phosphorylated CRTC2 is relocalized to the cytoplasm and CRTC2 target genes are down-regulated. Dysregulation of CRTC2 activity through over-expression of a nucleus-localized and constitutively active form of CRTC2 (CRTC2-AA) in human tonsillar B cells, prevented GC B cells from exiting the GC reaction and inhibited ASC differentiation. However, it remained unclear whether the function of CRTC2 in this in vitro differentiation system would be recapitulated in vivo and whether CRTC2 played any other roles in an in vivo humoral immune response.To evaluate these questions, we generated a transgenic (TG) mouse model which expresses CRTC2-AA at all stages of B cell development. Using these TG mice, we demonstrate that Crtc2 repression in PCs is an intrinsic requirement for PC metabolic fitness. Sustained CRTC2 activity shortened the survival of splenic and bone marrow PCs which resulted in the reduction of long-lived PCs and antibody deficits in response to immunizations and acute viral infection. We further demonstrated that TG PCs adopt characteristics associated with SLPCs which include reduced antibody secretion, glycolysis, oxidative metabolism, and spare respiratory capacity.Mechanistically, Crtc2 repression is necessary for the fidelity of PC gene expression and mRNA alternative-splicing programs, with both programs altered in TG PCs. Combined, our results show that Crtc2 repression in PCs must occur to support PC metabolism and extend PC survival and lifespan during a humoral immune response. We hypothesize that the level of Crtc2 repression in differentiated ASCs determines metabolic fitness and ultimately PC survival and longevity in the bone marrow.

ISBN: 9798645490317Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Crtc2 repression

CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses.
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300 $a 123 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
500 $a Includes supplementary digital materials.
500 $a Advisor: Teitell, Michael A.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a The humoral immune response is mediated by antigen activated B cells that have terminally differentiated into antibody secreting cells (ASCs). The ASC pool is composed of short-lived plasma cells (SLPCs) and long-lived plasma cells (LLPCs) that secrete antigen-specific antibodies to clear an infection and maintain long-term protective antibody titers to prevent subsequent reinfections. SLPCs have generally been viewed to be formed from T cell-independent immune responses and localized in the spleen. LLPCs have been viewed to be formed from T cell-dependent immune responses and localized in the bone marrow. However, regardless of the type of stimulating antigen, ASCs of varying lifespans, both SLPCs and LLPCs are found in the spleen and bone marrow. Currently, it remains unclear as to what factors and pathways regulate PC longevity.Our laboratory previously identified the CREB coactivator CRTC2 as a regulator of ASC differentiation. DNA double strand breaks associated with class switch recombination activates a signaling pathway in human germinal center (GC) B cells that results in the phosphorylation and inactivation of CRTC2. Phosphorylated CRTC2 is relocalized to the cytoplasm and CRTC2 target genes are down-regulated. Dysregulation of CRTC2 activity through over-expression of a nucleus-localized and constitutively active form of CRTC2 (CRTC2-AA) in human tonsillar B cells, prevented GC B cells from exiting the GC reaction and inhibited ASC differentiation. However, it remained unclear whether the function of CRTC2 in this in vitro differentiation system would be recapitulated in vivo and whether CRTC2 played any other roles in an in vivo humoral immune response.To evaluate these questions, we generated a transgenic (TG) mouse model which expresses CRTC2-AA at all stages of B cell development. Using these TG mice, we demonstrate that Crtc2 repression in PCs is an intrinsic requirement for PC metabolic fitness. Sustained CRTC2 activity shortened the survival of splenic and bone marrow PCs which resulted in the reduction of long-lived PCs and antibody deficits in response to immunizations and acute viral infection. We further demonstrated that TG PCs adopt characteristics associated with SLPCs which include reduced antibody secretion, glycolysis, oxidative metabolism, and spare respiratory capacity.Mechanistically, Crtc2 repression is necessary for the fidelity of PC gene expression and mRNA alternative-splicing programs, with both programs altered in TG PCs. Combined, our results show that Crtc2 repression in PCs must occur to support PC metabolism and extend PC survival and lifespan during a humoral immune response. We hypothesize that the level of Crtc2 repression in differentiated ASCs determines metabolic fitness and ultimately PC survival and longevity in the bone marrow.
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650 4 $a Cellular biology. $3 3172791
650 4 $a Immunology. $3 611031
650 4 $a Molecular biology. $3 517296
650 4 $a Pathology. $3 643180
653 $a Crtc2 repression
653 $a Humoral immune response
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710 2 $a University of California, Los Angeles. $b Cellular & Molecular Pathology 049D. $3 3550481
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