Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination

Svensson, Mattias; Andersson, Karin; Wasén, Caroline; Erlandsson, Malin C.; Nurkkala-Karlsson, Merja; Jonsson, Ing-Marie; Brisslert, Mikael; Bemark, Mats; Bokarewa, Maria

doi:10.1073/pnas.1514191112

Cited by 16 publications

(10 citation statements)

References 65 publications

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“…On the other hand, Flt3 is also expressed in some lymphoid progenitors. Although its function in this ontogeny branch has not been explored as profoundly, it plays a role in the early differentiation of B cells [21] and is re-expressed by B cells in the germinal center [22]. Moreover, new data indicate that the Flt3L/Flt3 axis is necessary for the development of NK and type 2 and 3 innate lymphoid cells [23] and their progenitors [24].…”

Section: Expression Pattern Of Flt3 and Flt3lmentioning

confidence: 99%

The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

Cueto

Sancho

2021

Cancers

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Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector activity, current immunotherapies should be directed to boost DC function. Herein, we review the potential function of Flt3L as a tool for cancer immunotherapy. Flt3L is a growth factor that acts in Flt3-expressing multipotent progenitors and common lymphoid progenitors. Despite the broad expression of Flt3 in the hematopoietic progenitors, the main effect of the Flt3/Flt3L axis, revealed by the characterization of mice deficient in these genes, is the generation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). However, Flt3 signaling through PI3K and mTOR may also affect the function of mature DCs. We recapitulate the use of Flt3L in preclinical studies either as a single agent or in combination with other cancer therapies. We also analyze the use of Flt3L in clinical trials. The strong correlation between type 1 cDC (cDC1) infiltration of human cancers with overall survival in many cancer types suggests the potential use of Flt3L to boost expansion of this DC subset. However, this may need the combination of Flt3L with other immunomodulatory agents to boost cancer immunotherapy.

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Section: Expression Pattern Of Flt3 and Flt3lmentioning

confidence: 99%

The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

Cueto

Sancho

2021

Cancers

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“…Even though the intracellular response to FL might be different for different lymphoid lineages, this common pattern of Flt3 downregulation upon commitment and maturation to functional lymphocytes seems to indicate that active Flt3 signaling possibly contributes to the maintenance of an “immature” lymphoid phenotype and therefore it needs to be silenced in order for mature lymphoid cells to become functional. There have been reports of Flt3 re-expression on mature, activated B cells [ 101 , 102 ] and activated human T cells [ 103 ]. For B cells, this could be the result of Pax5 downregulation, which is necessary for further differentiation to antibody secreting plasma cells.…”

Section: The Role Of Fl In Normal Hematopoiesismentioning

confidence: 99%

“…For B cells, this could be the result of Pax5 downregulation, which is necessary for further differentiation to antibody secreting plasma cells. Some evidence for a potential functional significance of Flt3 expression on activated lymphocytes has been reported [ 102 ] but further investigations are required to elucidate the exact role of FL in this context.…”

Section: The Role Of Fl In Normal Hematopoiesismentioning

confidence: 99%

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

Tsapogas

Mooney

Brown

et al. 2017

IJMS

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The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed.

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“…We found that CD11b was highly expressed to some extent after LPS stimulation, but there was no such change after anti-BCR stimulation (data not shown). TLRs on the surface of B cells are involved in the differentiation process of B cells in GC and induce the expression of AID, and it has been reported that LPS mediates long-term primary class-switched antibody responses and memory-like antibody responses in vivo ( 41 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

Intestinal CD11b+ B Cells Ameliorate Colitis by Secreting Immunoglobulin A

Wang

et al. 2021

Front. Immunol.

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The intestinal mucosal immune environment requires multiple immune cells to maintain homeostasis. Although intestinal B cells are among the most important immune cells, little is known about the mechanism that they employ to regulate immune homeostasis. In this study, we found that CD11b+ B cells significantly accumulated in the gut lamina propria and Peyer’s patches in dextran sulfate sodium-induced colitis mouse models and patients with ulcerative colitis. Adoptive transfer of CD11b+ B cells, but not CD11b−/− B cells, effectively ameliorated colitis and exhibited therapeutic effects. Furthermore, CD11b+ B cells were found to produce higher levels of IgA than CD11b− B cells. CD11b deficiency in B cells dampened IgA production, resulting in the loss of their ability to ameliorate colitis. Mechanistically, CD11b+ B cells expressed abundant TGF-β and TGF-β receptor II, as well as highly activate phosphorylated Smad2/3 signaling pathway, consequently promoting the class switch to IgA. Collectively, our findings demonstrate that CD11b+ B cells are essential intestinal suppressive immune cells and the primary source of intestinal IgA, which plays an indispensable role in maintaining intestinal homeostasis.

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Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination

Cited by 16 publications

References 65 publications

The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

Intestinal CD11b+ B Cells Ameliorate Colitis by Secreting Immunoglobulin A

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