Cyclin-Dependent Kinase Inhibitor <i>Cdkn2c</i> Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus

Potula, Hari-Hara S. K.; Xu, Zhiwei; Zeumer, Leilani; Sang, Allison; Croker, Byron P.; Morel, Laurence

doi:10.4049/jimmunol.1200556

Cited by 26 publications

(33 citation statements)

References 42 publications

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“…Similar to ATAμκTg.C.B17 mice, NZB mice have unique properties, since they exhibit thymocytotoxic autoantibody production started from early in life (58) and increased incidence of CD5 + B cell leukemia/lymphoma in aged mice (59). NZB mice contain significantly lower expression of the Cdkn2c gene encoding for p18 INK4c which is also the cyclin-dependent kinase inhibitor (60). In the NZB background, the presence of autocrine IL-10 by B1a cells was found to be critical for expansion to become lymphoma since IL-10 knockout strongly decreased CD5 + B lymphoma incidence (59).…”

Section: Discussionmentioning

confidence: 99%

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Hayakawa

Formica

Nakao

et al. 2018

The Journal of Immunology

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In mice, fetal/neonatal B-1 cell development generates CD5+ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a VH11/D/JH knock-in mouse line (VH11t) that generates an autoreactive anti-phosphatidylcholine (aPtC) B cell receptors (BCR). Our study revealed that aPtC B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN) and body cavity, as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel and blood. The body cavity-deposited B1a cells also re-migrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an anti-thymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eμ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgMhiIgDloCD5+CD23−CD43+ cells, resembling aggressive human mantle cell lymphoma (MCL). Thus, our findings reveal that early-generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and MCL-like neoplasia in aged mice.

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Section: Discussionmentioning

confidence: 99%

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Hayakawa

Formica

Nakao

et al. 2018

The Journal of Immunology

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“…As previously reported, p18 Ϫ/Ϫ mice display approximately 1.2-fold-increased cellularity, including increased homeostatic proliferation of peritoneal B1a cells, with accumulation over time (32). To determine whether p18 deficiency results in proliferation or skewing of potential reservoirs of infection, we quantified peritoneal B1a cells during infection.…”

Section: P18mentioning

confidence: 96%

“…INK4c plays distinct roles in hematopoietic development, autoimmunity, plasma cell differentiation, and tumorigenesis (32,39,40). Additionally, p18…”

Section: P18mentioning

confidence: 99%

“…INK4c related to the cell cycle, or does the v-cyclin manipulate another CDK-dependent process (e.g., B cell differentiation [31,32] or NF-B activation [48])? Second, does the v-cyclin bypass p18…”

Section: P18mentioning

confidence: 99%

“…INK4c has been implicated in differentiation in multiple cell types, including B cells, in a genetically nonredundant manner (31,32). p18…”

Section: P18mentioning

confidence: 99%

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A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18^INK4cTo Promote Reactivation from Latency

Williams

Niemeyer

Franklin

et al. 2015

J Virol

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Gammaherpesviruses (GHVs) carry homologs of cellular genes, including those encoding a viral cyclin that promotes reactivation from latent infection. The viral cyclin has reduced sensitivity to host cyclin-dependent kinase inhibitors in vitro; however, the in vivo significance of this is unclear. Here, we tested the genetic requirement for the viral cyclin in mice that lack the host inhibitors p27 Kip1 INK4c function in B lymphocytes, was also able to bypass the requirement for the viral cyclin in reactivation. These data show that the gammaherpesvirus viral cyclin functions specifically to bypass the cyclin-dependent kinase inhibitor p18INK4c , revealing an unanticipated specificity between a GHV cyclin and a single cyclin-dependent kinase inhibitor. IMPORTANCE The gammaherpesviruses (GHVs) cause lifelong infection and can cause chronic inflammatory diseases and cancer, especially in immunosuppressed individuals. Many GHVs encode a conserved viral cyclin that is required for infection and disease. While a common property of the viral cyclins is that they resist inhibition by normal cellular mechanisms, it remains unclear how important it is that the GHVs resist this inhibition. We used a mouse GHV that either contained or lacked a viral cyclin to testwhether the viral cyclin lost importance when these inhibitory pathways were removed. These studies revealed that the viral cyclin was required for optimal function in normal mice but that it was no longer required following removal or reduced function of a single cellular inhibitor. These data define a very specific role for the viral cyclin in bypassing one cellular inhibitor and point to new methods to intervene with viral cyclins.T he gammaherpesviruses (GHVs) include the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are associated with multiple lymphoproliferative and inflammatory diseases (1). Gammaherpesvirus 68 (GHV68) (or murine herpesvirus type 4 [MuHV-4]) infects laboratory mice and provides a small-animal model for these infections and diseases, as it allows examination of all stages of infection, using both wild-type (WT) and mutant viruses and mice (2).The GHVs have an intimate relationship with cells of the immune system. The GHVs establish lifelong infection in cells of the immune system, primarily B cells, and exploit the natural lifestyle of B cells for their maintenance and propagation (3). Primary GHV infection results in production of virus and lysis of many cells. Acute infection is controlled by the immune response in a healthy host, so that within 2 weeks postinfection (p.i.), only latent infection can be detected. Latent, or quiescent, infection is exquisitely attuned to the host cells and is typified by very low levels of viral gene expression in cells that harbor the viral genome. Latently infected cells retain the capacity to reactivate from latency, to express the full complement of viral genes, and to make new virus. Reactivation from latency is one mechanism contributing t...

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SLy2 controls the antibody response to pneumococcal vaccine through an IL‐5Rα‐dependent mechanism in B‐1 cells

et al. 2014

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The adaptor protein SLy2 (Src homology domain 3 lymphocyte protein 2) is located on human chromosome 21 and was reported to be among a group of genes amplified in Down's syndrome (DS) patients. DS patients characteristically show an impaired immunity to pneumococcal infections. However, molecular mechanisms linking gene amplifications with specific DS phenotypes remain elusive. To investigate the effect of SLy2 gene amplification on the mammalian immune system, we studied SLy2 overexpressing transgenic-SLy2 (TG) mice. We found that baseline immunoglobulin M (IgM) levels as well as IgM responses following Pneumovax immunizations were reduced in TG mice. Moreover, B-1 cells, the major natural IgM-producing population in mice, were reduced in the peritoneal cavity of TG mice, while other immune cell compartments were unaltered. Mechanistically, SLy2 overexpression attenuated the expression of the IL-5 receptor α chain on B-1 cells, resulting in decreased B-1 cell numbers and decreased differentiation into Ab-secreting cells. Since B-1 cells essentially contribute to immunity against Streptococcus pneumoniae, the present study provides a novel molecular link between SLy2 expression and pneumococcal-specific IgM responses in vivo. These studies suggest that the adaptor protein SLy2 is a potential future target for immunomodulatory strategies for pneumococcal infections.

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Cyclin-Dependent Kinase Inhibitor Cdkn2c Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus

Cited by 26 publications

References 42 publications

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18^INK4cTo Promote Reactivation from Latency

SLy2 controls the antibody response to pneumococcal vaccine through an IL‐5Rα‐dependent mechanism in B‐1 cells

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Cyclin-Dependent Kinase Inhibitor Cdkn2c Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus

Cited by 26 publications

References 42 publications

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18INK4cTo Promote Reactivation from Latency

SLy2 controls the antibody response to pneumococcal vaccine through an IL‐5Rα‐dependent mechanism in B‐1 cells

Contact Info

Product

Resources

About

A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18^INK4cTo Promote Reactivation from Latency