bluuebunny/crossref_metadata_2025_split huggingface dataset:
A molecular mechanism for the increased degradation of E47 mRNA in old murine B cells involves TTP (tristetraprolin) (83.5)
Authors: frasca daniela , landin ana marie , alvarez juan p , riley richard l , blomberg bonnie b 
Published: January 2023

Abstract
We have previously shown that the E2A-encoded transcription factor E47, which regulates class switch recombination (CSR) in splenic B cells, is down-regulated in aged murine B cells, due to increased E47 mRNA decay. At least part of the decreased stability of E47 mRNA seen in aged B cells is mediated by cytoplasmic proteins increased in aged activated B cells. This is the first study to show that TTP is involved in the degradation of E47 mRNA TTP binds AU-rich elements in the 3′-untranslated region (3′-UTR) of mRNAs leading to their rapid degradation. We show herein that TTP mRNA and protein expression are induced by LPS, anti-CD40 and to a lesser extent by anti-IgM, in B cells from young and old mice. The level of TTP in old B cells is always higher than that in young B cells. We found TTP protein expression and function in B cells are dependent upon p38 MAPK and there is less phospho-p38 in old activated B cells. Also there is less phospho-TTP in old than in young splenic activated B cells, which leads to more binding of TTP to the 3′-UTR, therefore decreasing mRNA stability in old B cells. These molecular mechanisms for the regulation of E47 in B cells are important for understanding the control of AID, CSR, and somatic hypermutation of Ig, critical for high affinity Ig and optimal response to pathogens.
HEBAlt: a potent transcriptional regulator of proliferation in developing B cell precursors (83.8)
Authors: Anderson Michele Kay , Wang Duncheng , Claus Carol L. 
Published: January 2023

Abstract
The basic helix-loop-helix transcription (bHLH) factor E2A is essential for B cell development, and can act as a homodimer or as a heterodimer with the closely related bHLH factor HEB. We have identified a short form of HEB called HEBAlt, which differs from the long form of HEB in its structure, function, and regulation, and which is conserved in vertebrates, including humans. Within hematopoiesis, HEBAlt is expressed only in developing T cell and B cell precursors. HEBAlt is strongly upregulated in pre-B cells, but is absent in IgM+ B cells. Retroviral expression of HEBAlt in multipotent hematopoietic precursors partially blocks B cell development. However, committed B cell precursors expressing ectopic HEBAlt undergo rapid expansion and exhibit extended survival in culture. HEBAlt-induced expansion arises from a limited number of precursors, indicating that secondary events collaborate with HEBAlt to cause loss of growth control. IL-7R and cyclin D3 are upregulated in HEBAlt-transduced cells, suggesting that HEBAlt normally functions to promote proliferation of early B cell precursors. Furthermore, downregulation of HEBAlt may be required for quiescence during Ig light chain rearrangement. These results suggest that dysregulation of HEBAlt could play an initiating role in the oncogenic transformation of B cell precursors.
A critical role for DRAK2 in the germinal center reaction and the antibody response (84.1)
Authors: Al-Qahtani Ahmed , Xu Zhenming , Walsh Craig , Casali Paolo 
Published: January 2023

Abstract
DRAK2 (DAP-related apoptotic kinase-2) protein is a DAP family member. DRAK2 is highly expressed in B and T lymphocytes and it is among the few proteins that are highly enriched in the lymphoid system. To determine whether DRAK2 plays a role in B cell activation and differentiation, we analyzed the germinal center development in the spleen of drak2−/− mice immunized with a T cell-dependent (TD) antigen. Immunofluorescence microscopy and FACS analysis showed the number of germinal centers was three to five-folds less in the drak2−/− mice than in their wild type littermates. Impairment of germinal center development was not due to a deficiency in B cell proliferation, as BrdU uptake in vivo and CFSE staining ex vivo of B cells was comparable in DRAK2-deficient and wild type B cells. 7-AAD and TUNEL staining experiments showed that, the proportion of apoptotic germinal center B and T cells in drak2−/− mice was significantly higher than wild type mice. As a result, the generation of high affinity IgG antibodies was impaired in drak2−/− mice. Specific expression of bcl-xl in T cells of drak2−/− mice rescued germinal center formation. Thus, our findings suggest a novel role of DRAK2 in the germinal center reaction and the maturation of the antibody response.
Supported by N.I.H. grants AR 40908, AI 45011 and AI 60573.
Calcitonin Gene-Related Peptide (CGRP) Inhibits Apoptosis by Differential Phosphorylation of BAD Serines 112, 136 and 155 (84.12)
Authors: Ciornei Radu Tudor , McGillis Joseph P 
Published: January 2023

Abstract
Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that inhibits early B cell differentiation. It enhances B cell survival by upregulating Pim-1, a S/T kinase that regulates Bcl-2 expression, and by shifting expression of Bcl-2 family members to anti-apoptotic members. Studies were done to further characterize CGRP’s effect on Bad phoshorylation. Inactive Bad (a pro-apoptotic Bcl-2 family member) is phosphorylated at ser112, ser136, and ser155 by different mechanisms. Bad ser112is a Pim-1 target. Dephosphorylated Bad forms heterodimers with Bcl-XL and Bcl-2, blocking their anti-apoptotic effects. Studies were done to determine if CGRP influences Bad phosphorylation. 70Z/3 cells were grown in low serum and treated with CGRP. Bad phosphorylation at ser112, ser136 and ser155 was measured by western blot. Serum starvation decreased Bad phosphorylation at 4 hrs and completely depletes phospho-Bad at 24 hours. CGRP upregulated phospho-ser112 and -ser155, peaking at 8–12 hrs and returning to untreated levels at 24 hrs. The results show that CGRP induced Bad phosphorylation at ser112 and ser155 is correlated with increased Pim-1 expression. In contrast, CGRP had no effect on ser136phosphorylation. This study provides further information on cellular and molecular mechanisms underlying CGRP’s protective effect in immature B cells.
A study of the signaling pathway and effector mechanisms of TNF-induced programmed necrosis (84.13)
Authors: Ray Tathagat Dutta , Chan Francis 
Published: January 2023

Abstract
TNF-induced programmed necrosis is an alternate form of cell death that occurs when caspase activation is inhibited. In this study, we have examined the signaling complexes formed during programmed necrosis in jurkat cells. We show that RIP is recruited to the membrane complex with similar kinetics in cells undergoing programmed necrosis and apoptosis. However, ubiquitination of RIP is diminished in programmed necrosis in comparison to apoptosis. We also show that caspase8 dependent cleavage of RIP within the cytosolic complex is inhibited during programmed necrosis. This inhibition of RIP cleavage is crucial for it’s kinase activity, which is essential for the induction of programmed necrosis. We also show that unlike necrosis induced by oxidative stress and macromolecular synthesis inhibitors in fibroblasts, TNF-induced programmed necrosis does not require either ROS or Jnk activation. This shows that the process of programmed necrosis can be mediated by distinct effector mechanisms in different cell types. Our study provides some important insights into the process of TNF-induced programmed necrosis.
Pax5 acts as a negative regulator for p53 (84.2)
Authors: Zhang Zhixin , Park Seayoung , Zhou Jianping , Chen Xinbin , Yu Zhihong 
Published: January 2023

Abstract
Pax5/BSAP is an important regulator for B lineage cell development and function. Pax5 activates many B lineage specific genes expression, suppresses lineage non-appropriate genes expression, and controls B lineage specific immunoglobulin gene VH→DJH recombination. On the other hand, abnormal Pax5 expression has been found in different type of tumors, suggesting that Pax5 might have oncogenic potential. It has been previously shown that Pax5 interferes with p53 function through inhibition p53 gene transcription. Here, we show that Pax5-inhibits p53-meidated induction of different p53-responsive reporter genes without affecting the p53 protein expression level; conversely, forced expression of p53 or activation of p53 by DNA damaging response also suppresses Pax5-mediated transcriptional activation. Co-immunoprecipitation studies provide the evidence that Pax5 interacts with p53, which is essential for the mutual functional interference between these two factors. Moreover, overexpression of Pax5 attenuates DNA damage induced p53 Ser-18 phosphorylation and inhibits p53-medaited induction of downstream target genes, including p21, Bax, Puma, and Gadd45α. Through interfering p53 function, overexpression of Pax5 protects cells from DNA damage induced apoptosis. These results reveal that Pax5 acts as a negative regulator for p53, which might be essential for the dual roles of Pax5 in B lymphopoiesis and tumorigenesis.
The function of the putative tumor suppressor Nit1 in lymphocytes (84.7)
Authors: Zhang Jianke , Zhang Haibing 
Published: January 2023

Abstract
The mammalian Nit1 gene is homologous to bacterial and plant nitrilases. In the fruit fly D. melanogaster and warms C. elegans, Nit1 is fused to the Fhit gene, whereas in mammals, FHIT and NIT1 are separate genes. FHIT is a tumor suppressor gene located at chromosome region 3p14.2, encompassing the common fragile site of the human genome. Somatic loss of Fhit in humans is associated with cancers in a wide variety of sites, including lung, kidney, stomach, pancreas, cervix, ovary, head and neck, breast, and hematopoetic cells. Proteins that engage in fusion events are expected to jointly participate in a biochemical or cellular pathway and/or to physically interact. Therefore, Nit1 may be functionally related to Fhit. Overexpression of Fhit and Nit1 can induce apoptosis. There was evidence showing that Fhit can induce FADD-mediated cell death. In this study, the in vivo function of Nit1 was analyzed using the Nit1 knockout mice. Various in vitro and in vivo analyses showed that Nit1 plays an important role in regulating cell cycle and proliferation in T lymphocytes.
Aged mice demonstrate altered regulation of distinct B cell developmental pathways (85.10)
Authors: Wolf Sarah , Blomberg Bonnie , Riley Richard 
Published: January 2023

Abstract
Three precursor subsets in bone marrow that generate new B cells were identified in young and aged (20–22 mo.) adult mice. The major subset (c-kit neg) is reduced in aged mice while minor c-kit+ and B1 lineage precursors are better maintained. In vitro, the c-kit+ and B1 precursors more readily generate B cells that undergo spontaneous activation. We suggest that altered levels of these precursors contribute to changes in B cell production and bias to activated phenotypes in aged mice. The “aged phenotype” of few c-kit neg, but maintained c-kit+/B1 precursors, is mimicked in young adult lambda 5 gene knockout mice as are the alterations in new B cell development. Therefore, the preBCR promotes development of c-kit neg B cell precursors, but is not necessary for c-kit+ and B1 precursors. Lambda 5 is decreased in aged B cell precursors, together with E2A. This suggests the hypothesis that, in aged mice, poor preBCR expression interferes with development of c-kit neg B precursors, but not c-kit+/B1 precursors. This, in turn, contributes to changes in the number, specificity, and function of new B cells generated in senescent bone marrow.
Supported by NIH grants AI 064591 and AG 025256 to RLR
Involvement of immunosenescence in the frailty syndrome (85.13)
Authors: morrhaye gabriel , Bruck France , de Saint-Hubert Marie , Weemaels Geoffroy , Swine Christian , Toussaint Olivier , Geenen Vincent , Martens Henri 
Published: January 2023

Abstract
A determinant factor of immunosenescence is the involution of the T-cell compartment, due to a decline in thymic generation of a diverse T-cell repertoire, as well as in peripheral T-cell homeostasis.
Human immunosenescence was investigated through measurement of telomere length by Q-PCR, evaluation of thymic output by Sj and VβTREC methodology, analysis of T-cell phenotype profile, and multiplex cytokine production after polyclonal stimulation. The diseases scrutinized in the elders were pneumonia, heart failure and hip fracture.
TREC value was negatively correlated with age, but no significant relationship could be evidenced with pathological states. A significant rise in pro-inflammatory cytokines IL-6, IFNγ and TNFα was observed in elderly vs. young controls, while IL-10 was significantly decreased. The cytokine profiles as analyzed by protein array showed at least three different patterns: either increased in elderly vs. young and decreased in pathologic states, either increasing or showing no modifications in all cases.
A significant shortening of telomere length in the elderly was observed when compared to young controls. There was a significant decrease between healthy and sick elders.
Significant correlations were evidenced between morbidity and some immune parameters, supporting that immunosenescence contributes to the frailty syndrome.
Supported by the Walloon Region - Senegene project
Recall immune memory in old baboons and mice: implications for vaccine design (85.18)
Authors: Stacy Sue , Dube Peter H. , Kraig Ellen 
Published: January 2023

Abstract
While primary antibody responses are often lower in old individuals, immune memory can survive aging and be vigorously recalled. We assessed whether these long-lived responses might impact vaccine antibody responses in the elderly. Three groups of baboons were tested: young controls, old animals inoculated with tetanus vaccine when young, and old baboons not previously exposed to tetanus. Each group received either a chimeric vaccine, TTFC (tetanus toxin fragment C, the recall antigen) linked to LcrV (a protective plague antigen) or LcrV alone. Among old baboons receiving the chimeric protein, those with previous exposure to tetanus had lower anti-LcrV antibody responses. Unexpectedly, old baboons receiving LcrV only (no tetanus exposure) had higher antibody responses and protective indices than the young; thus, the aging baboon immune system may be atypical. By contrast, aging mice responded as expected; the old mice had lower responses to LcrV compared with young mice. In recall tests, among old mice inoculated LcrV-TTFC, those with previous TTFC exposure had altered anti-LcrV antibody titers; the response was depressed or enhanced depending upon the dose of chimera given. Therefore, caution may be warranted when using subunit vaccines with components that recall previous exposures.
Support: the Nathan Shock Center, a Southwest National Primate Research Center pilot grant, a UTHSCSA PREF grant, and NIH [R03 AG 14557 (EK) and R03 AG 22675 (SS)].
Aged Micro-environment Severely Impairs Specific CD8 T Cell Response to Virus Infection (85.21)
Authors: Jiang Jiu , Bennett Andrew J. , Murasko Donna M. 
Published: January 2023

Abstract
Both intrinsinc and extrinsinc factors are considered to affect immunity with aging. However, few studies have reported that the aged micro-environment affects the specific CD8 T cell response to primary virus infection. In this study, we adoptively transferred CFSE-labeled young P14 cells (2-month-old) into young (4-month-old) and aged (24-month-old) mice. The recipients were infected with LCMV (Arm strain) and the Db-GP33–41 specific CD8 T cell response in the spleen was examined for virus specific responses using flow cytometric analysis of Db-GP33–41 tetramer binding and intracellular IFN-γ production at different times after infection. No obvious expansion of the P14 cells was observed on days 1 and 2 after infection in either age group. However, on day 3 post-infection, extensive expansion of P14 cells was observed in young, but not aged, recipients (increased percentage: young vs aged: 275% vs 18%). Coincidentally, 68% percent of CD8 T cells of young recipients were depleted, while no CD8 T cells of aged recipients were depleted on day 3. These results confirm our previous data with E55+MuLV infection, that non-specific depletion of CD8 T cells occurs early after infection in young but not aged mice, and support the hypothesis that this lack of depletion contributes to the hyporesponsiveness of aged mice. While our previous data demonstrated that the aged environment limits the depletion of T cells of young mice, the current data expands these findings by suggesting that the aged environment also limits expansion of virus-specific T cells of young mice.
This work was supported by National Institute of Health Grant AG14913 to D. M. M.
Cytokine adjuvants enhance the cognate helper function of aged CD4 T cells (85.22)
Authors: Eaton Sheri M , Maue Alexander C , Blumerman Seth L , Haynes Laura 
Published: January 2023

Abstract
The elderly exhibit reduced responses to vaccinations, leaving them more susceptible to preventable infectious diseases such as influenza and pneumonia. When the aged are vaccinated, the resulting antibody titers are lower than those seen in younger individuals and the function of the antibodies produced is also diminished. We have examined how reductions in CD4 T cell function contribute to reduced humoral responses, using an adoptive transfer model which allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) mice. Naive CD4 T cells from aged Tg mice exhibit significantly reduced cognate helper function, leading to reduced B cell expansion and differentiation and reduced antibody production, even in young hosts. The cognate helper function of these aged Tg CD4 T cells can be enhanced significantly by prior effector generation with a cytokine cocktail containing TNFalpha, IL-1 and IL-6 (T16) or by using this cocktail as an adjuvant for immunization. Using this cocktail, enhanced B cell responses, including significantly higher antibody titers, are observed. Gene expression analysis shows that T16 enhances CD40L expression by the aged CD4 T cells, possibly accounting for the enhanced cognate function. Importantly, this cocktail also enhances humoral responses in intact aged animals. These results suggest that the efficacy of vaccines for the elderly can be enhanced by use of appropriate adjuvants.
Supported by NIH grants AG21054 and AG02160 to LH.
The effect of aging on CD4+ Foxp3+ T cells in humans (85.23)
Authors: Kang Insoo , Kim Hang-Rae , Hwang Kyung-A 
Published: January 2023

Abstract
Foxp3 is critical for regulatory-T cell function. Although alterations in immunity occur with aging, little is known how aging affects the number, phenotypes and function of CD4+ Foxp3+ T cells in humans. Here, we report that CD4+ Foxp3+ T cells are largely CD4+ CD25bright T cells in healthy elderly (age¡Ã65) and young individuals (age¡Â40) and that the two groups have comparable frequencies of CD4+ Foxp3+ T cells. Although CD4+ Foxp3+ T cells mostly have a memory phenotype (CD45RA-) in both groups, the frequency of such cells was higher in the elderly. However, CD4+ Foxp3+ T cells from the two groups similarly express CTLA-4 which has immunosuppressive function as well as receptors (R) for chemokines (CCR4, CCR5, CXCR3 and CCR7) and cytokines (IL-15Ra, IL-2/-15Rb and IL-7Ra) which are involved in T cell trafficking and maintenance, respectively. More importantly, the inhibitory effect of CD4+ CD25bright T cells expressing Foxp3+ on CD4+ CD25− T cells was not different between the two groups as measured by cell proliferation, IFN-g and IL-10 production. Our study indicates that aging does not affect CD4+ T cell immune regulation by CD4+ Foxp3+ T cells and that therapeutic strategies targeting the latter cells can be considered regardless of age.
Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune uveoretinitis (EAU) and recruitment of pathogenic ThIL17 and Th1 cells into the retina (85.29)
Authors: Liu Xuebin , Lee Yunsang , Yu Cheng-rong , Silver Phyllis , Caspi Rachel , Igal Gery , Charles Egwuagu E 
Published: January 2023

Abstract
ThIL17 cells are implicated in etiology of several inflammatory and autoimmune diseases. Although recent reports have emphasized essential roles of IL-6 and TGF-β1 in promoting commitment of naive CD4+ cells into ThIL17 lineage, their exact roles or contributions to development of ThIL17 cells is not well understood. IL-6 is a pleiotropic cytokine that mediates some of its biological activities through STAT3. In this study we have used a mouse with targeted deletion of STAT3 in CD4+ cells to investigate whether ThIL17 development or their involvement in pathogenic mechanisms of experimental autoimmune uveoretinitis (EAU) requires STAT3. In wild type (WT) mice, EAU is characterized by infiltration into the retina of ThIL17 and Th1 cells that express high levels of VLA-4 and LFA-1. In contrast, STAT3 conditional knockout (STAT3KO) mice do not develop EAU, fail to differentiate into ThIL17 cells, express low levels of VLA-4/LFA-1 integrins and do not enter the eye. Moreover, TGF-β1 and IL-6 or IL-23 are unable to induce naive STAT3KO T cells to differentiate into ThIL17 cells, providing further evidence that STAT3 is indispensable for commitment to the ThIL17 lineage. The requirement of STAT3 for integrin expression and the defective recruitment of IRBP-primed STAT3KO Th1 and ThIL17 cells into the eye during EAU, suggest that STAT3 is a potential target for therapeutic modulation of uveitis and other CNS inflammatory diseases.
Functional Significance of PD-1 expression on aging T cells (85.4)
Authors: Suvas Susmit , Joo Hye Mee , Sehrawat Sharvan , Suvas Pratima Krishna , Sangster Mark Y , Yagita Hideo , Azuma Miyuki , Rouse Barry T 
Published: January 2023

Abstract
Increasing age is associated with the lesser ability of T and B cells to mount an effective immune response against the microbial antigens. Numerous reports have documented the malfunctioning of the different components of immune system with aging but a more detailed mechanistic understanding of the age associated immunological changes in the elderly individuals is needed to develop better vaccines specific for this population. In this study, we observed that PD-1, a key inhibitory receptor in chronic viral infections, was highly expressed on T cells from uninfected aged but not young mice. Next, we determined if PD-1 expression on T cells regulate adaptive immune responses in aged animals. Young and old groups of mice were treated with anti-PD1 or anti-PDL1 mAbs prior to HSV-1 or influenza A virus infection. Our results showed a significant increase in the number of HSV-1 or Influenza specific CD8+ T cells during acute and secondary expansion of memory CD8+ T cells in the aged mice group when compared with control infected aged animals. Furthermore, a significant increase in the number of flu-specific ASCs (antibody secreting cells) and memory B cells was clearly evident in the spleen of antibody treated aged animals in comparison to the control infected aged mice group.
Supported by NIAID-AI-063365 grant