Follicular B Cell Trafficking within the Spleen Actively Restricts Humoral Immune Responses

Hoek, Kristen L.; Gordy, Laura E.; Collins, Patrick L.; Parekh, Vrajesh V.; Aune, Thomas M.; Joyce, Sebastian; Thomas, James W.; Kaer, Luc Van; Sebzda, Eric

doi:10.1016/j.immuni.2010.07.016

Cited by 58 publications

(76 citation statements)

References 51 publications

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“…We have previously demonstrated that KLF2 differentially impacts lymphocyte homeostasis in a lineage-specific manner (17). Therefore, we decided to examine iTreg and tTreg development independent of one another.…”

Section: Klf2 Is Required For the Ex Vivo Generation Of Itregsmentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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Section: Klf2 Is Required For the Ex Vivo Generation Of Itregsmentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, the role of Klf2 in B cell development has been examined in some detail (6)(7)(8). In the absence of Klf2, there is a reduction in recirculating B cells in the bone marrow and a significant increase in the number of MZ B cells in the spleen.…”

Section: Trafficking and Homing Of B Cells In Klf3 Null Micementioning

confidence: 99%

Impaired B Cell Development in the Absence of Krüppel-like Factor 3

Vũ

Gatto

Turner

et al. 2011

The Journal of Immunology

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Krüppel-like factor 3 (Klf3) is a member of the Klf family of transcription factors. Klfs are widely expressed and have diverse roles in development and differentiation. In this study, we examine the function of Klf3 in B cell development by studying B lymphopoiesis in a Klf3 knockout mouse model. We show that B cell differentiation is significantly impaired in the bone marrow, spleen, and peritoneal cavity of Klf3 null mice and confirm that the defects are cell autonomous. In the bone marrow, there is a reduction in immature B cells, whereas recirculating mature cells are noticeably increased. Immunohistology of the spleen reveals a poorly structured marginal zone (MZ) that may in part be caused by deregulation of adhesion molecules on MZ B cells. In the peritoneal cavity, there are significant defects in B1 B cell development. We also report that the loss of Klf3 in MZ B cells is associated with reduced BCR signaling strength and an impaired ability to respond to LPS stimulation. Finally, we show increased expression of a number of Klf genes in Klf3 null B cells, suggesting that a Klf regulatory network may exist in B cells.

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“…KLF2 partially appears to possess functions that are opposing to those of KLF3, such as in the generation of MZ B cells or lower b 7 expression in KLF2-deficient B cells (15,16,19). Indeed, upon KLF2 overexpression in P815 cells, b 7 expression is increased (Fig.…”

Section: Klf3 Represses and Klf2 Upregulates B 7 Integrin Expression mentioning

confidence: 95%

“…In lymphocytes, KLFs play important roles in their development and function (7,9,(13)(14)(15)(16)(17)(18)(19)(20). When constitutively expressed under the B cell-specific CD19 promoter, KLF3 increases maturation toward marginal zone (MZ) B cells, resulting in a 5-to 10-fold increase of this subset, whereas, accordingly, MZ B cells were reduced in KLF3-deficient mice (7,9).…”

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confidence: 99%

“…When constitutively expressed under the B cell-specific CD19 promoter, KLF3 increases maturation toward marginal zone (MZ) B cells, resulting in a 5-to 10-fold increase of this subset, whereas, accordingly, MZ B cells were reduced in KLF3-deficient mice (7,9). Interestingly, absence of KLF2 in B cells results in an increase of MZ B cells, mimicking the effect of constitutive KLF3 expression (15,16,19). Although the actual target genes mediating this effect are unknown, it has been demonstrated that the lymphocyte phenotypes of KLF2-deficient mice result from effects on the positioning, recirculation, and/or tissue-homing ability of these cells (13,14,19,(21)(22)(23)(24).…”

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confidence: 99%

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Leukocyte β7 Integrin Targeted by Krüppel-like Factors

Alles

Turchinovich

Zhang

et al. 2014

The Journal of Immunology

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Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin β7 (Itgb7, Ly69) by binding to the β7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the β7 promoter, indicating that these factors may compete for target sequence(s). Whereas β7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because β7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when β7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer’s patches, much like β7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of β7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of β7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.

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Follicular B Cell Trafficking within the Spleen Actively Restricts Humoral Immune Responses

Cited by 58 publications

References 51 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Impaired B Cell Development in the Absence of Krüppel-like Factor 3

Leukocyte β7 Integrin Targeted by Krüppel-like Factors

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