bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD40 on T cells interacts with CD154 to promote autoimmune diabetes (101.7)
Authors: Baker Rocky , Mallevaey Thierry , Gapin Laurent , Haskins Kathryn 
Published: January 2023

Abstract
Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells mediated by self-reactive CD4 T cells. Our objective in this study was to determine how CD40 on autoreactive CD4 T cells contributes to their pathogenicity. BDC-5.2.9 is a highly diabetogenic CD4 T cell clone and expresses the costimulatory molecule CD40 which can interact with CD154, also expressed on T cells. To investigate signaling through CD40 on T cells, we produced a variant of the diabetogenic T cell clone BDC-5.2.9 expressing a dominant-negative (DN) form of the CD40 molecule. In vitro, we demonstrated that activated T cells express both CD40 and CD154 on their surface and that these two molecules interact when on the same cell. Engagement of CD154 on activated T cells with CD40 on resting T cells resulted in activation of bystander CD40-positive T cells. Transactivation did not occur when clones were transduced with CD40DN, indicating that CD40 engagement on T cells was necessary for transactivation. Furthermore, when the CD40DN variant of BDC-5.2.9 was tested in vivo, none of the recipients developed diabetes. Ex vivo analysis of the pancreatic infiltrate after transfer of BDC-5.2.9 CD40DN revealed an overall reduction of cytokines produced by T cells in addition to decreased activation and function of recruited macrophages. Our data suggest that targeting CD40 expressed on T cells could be a potential avenue for immunotherapy in T1D.
A novel final step in leukocyte extravasation (102.19)
Authors: Hyun Young-Min , Sumagin Ronen , Sarangi Pranita , Overstreet Michael , Baker Christina , Fowell Deborah , Sarelius Ingrid , Kim Minsoo 
Published: January 2023

Abstract
The real-time dynamics of cell surface adhesion receptor reflect leukocyte migration and trafficking in lymphoid and non-lymphoid tissues, providing valuable insight into the evolving events of the immune response. Despite notable advances in studying leukocyte migration in simplified systems in vitro, live imaging of subcellular adhesion complexes expressed at physiological density in intact tissues has been challenging. To this end we generated a knock-in mouse with CD18 fused to CFP. To enable imaging of CD18 dynamics during transendothelial migration of T lymphocytes, monocytes, and neutrophils, we used multiphoton-intravital microscopy and enhanced three dimensional detection of the fluorescent CD18 fusion protein. These in vivo analyses and parallel experiments in vitro show that extravasating leukocytes become extremely elongated before completing transmigration across the endothelium and subsequent retraction of the stretched uropod from the basolateral side of the endothelial cells takes longer than 20 min, occasionally leaving CD18-enriched microparticle at the basement membrane. Experiments with knock-out mice and blocking antibodies reveal that the uropod elongation is mediated by LFA-1. Therefore we propose that uropod elongation/delayed tail retraction is a novel final, rate-limiting step in the leukocyte extravasation cascade, which may be important for precise regulation of leukocyte recruitment and maintaining endothelial barrier function during inflammation.
CCL18-mediated pulmonary infiltration of T lymphocytes is independent of TRAIL but requires DR5 (102.20)
Authors: Luzina Irina , Atamas Sergei , Lockatell Virginia , Rus Violeta 
Published: January 2023

Abstract
Activities of T lymphocytes are centrally regulated by interactions between multiple members of the TNF/TNF-R family. TRAIL is a member of the TNF family with pro-apoptotic activity. The only signaling TRAIL receptor in mice is death receptor (DR) 5. CCL18, a chemokine with selective chemotactic activity on T lymphocytes, is known for its involvement in pulmonary inflammation and fibrosis associated with autoimmune diseases. We measured soluble TRAIL in bronchoalveolar lavage (BAL) fluids. The levels of TRAIL were significantly elevated (p &lt; 0.01, ANOVA) in BAL from 16 patients with scleroderma lung disease (211±110 pg/ml) compared to 16 patients without lung involvement (115±58 pg/ml), or 8 healthy controls (73±41 pg/ml). To determine whether TRAIL is important for CCL18-induced pulmonary infiltration of lymphocytes, recombinant adenovirus-mediated gene delivery of CCL18 was performed in TRAIL KO, DR5 KO, and WT mice. Overexpression of CCL18 caused profound pulmonary lymphocytic infiltration in WT and TRAIL KO mice, compared to control mice infected with AdV-NULL. In contrast, infiltration of T lymphocytes was completely abrogated in CCL18-expressing DR5 KO mice, based on lung histology. Thus, the levels of TRAIL are elevated in the lungs of patients with autoimmunity-associated inflammation and fibrosis, yet TRAIL does not appear to be involved in the CCL18-mediated T lymphocytic infiltration, whereas its receptor DR5 is required for such T cell response to CCL18.
Lipocalin-2 is involved in immune-complex mediated inflammation (102.23)
Authors: Shashidharamurthy Rangaiah , Parkos Charles , Selvaraj Periasamy , Vijay-Kumar Matam 
Published: January 2023

Abstract
Lipocalin-2 (Lcn-2) is an innate immune protein whose expression is upregulated by several orders of magnitude in response to inflammation/injury/infection by variety of cells including neutrophils. However, the role of Lcn-2 induction in IC-induced inflammation is largely unknown. Here in, we have investigated the role of Lcn-2 during IC-mediated inflammation using Lcn-2 knock out (Lcn-2KO) and wild type (WT) mice. IC-mediated inflammation upregulated systemic Lcn-2 in WT mice when compared to naïve mice. The neutrophil chemoattractant KC was significantly elevated in WT, but not in Lcn-2KO mice, in response to IC-induced inflammation. Consistently Lcn-2KO mice showed about 50% reduced IC-mediated inflammation when compared to WT mice. Histopathological analysis of skin biopsy showed reduced inflammatory cell infiltration at inflamed site in Lcn-2KO mice relative to WT mice. Administration of recLcn-2 into Lcn-2KO mice resulted in inflammation similar to that of WT mice in response to IC. Lastly, we observed that neutralization of Lcn-2 via neutralizing mAb significantly reduced inflammation in WT mice. These results suggest that engagement of FcγRs expressed on local inflammatory cells with ICs leads to the induction of Lcn-2. Such IC-induced Lcn-2 expression may be essential for infiltration inflammatory cells at the site of inflammation. Our studies show that therapeutic targeting of Lcn-2 may be useful approach for treating IC-mediated inflammatory/autoimmune diseases
CD8 T cells are rapidly recruited to both immunized and unimmunized skin after vaccinica virus skin scarification persist long-term as nonmigratory resident memory T cells (Trm), and provide rapid, effective, and specific local immunity (102.25)
Authors: Jiang Xiaodong , Wagers Amy , Clark Rachael , Liu Luzheng , Fuhlbrigge Robert , Kupper Thomas 
Published: January 2023

Abstract
Abundant Trm populate normal, non-inflamed skin in both humans and mice, but little is known about their trafficking patterns. We created parabiotic mice by joining wild-type (WT) mice with GFP-transgenic mice. These mice rapidly developed a shared a circulatory system, with equilibration of GFP+ and GFP- T cells in blood and lymphoid tissues (LT), but this never occurred in skin. To test the trafficking of CD8 Trm, we s.s. immunized OT-1 bearing mice with VACV that expressed ovalbumin (VACV-OVA). Five weeks after s.s., we joined these mice parabiotically with naive mice. After 2 weeks, central memory (Tcm) OT-1 cells had equilibrated in blood and LT. However, OT-1 skin Trm could only be detected in the immunized parabiont, even after 24 weeks of parabiosis. When B-cell-deficient (µMT) mice for parabiosis (both immunized and naïve), we found that the skin of the immunized but not the naïve mouse rapidly cleared virus on challenge. These data suggest that CD8+ Trm can persist in previously infected skin and do not readily migrate out of skin. Next we asked whether uninfected skin of immunized mice contained OT-1 Trm. We could find substantial numbers of OT-1 Trm cells in uninfected skin; this number increased further after multiple infections. VACV was rapidly cleared from uninfected skin of s.s. immunized mice after challenge. Our results demonstrate that CD8+ Trm cells persist long term in the skin of s.s. immunized mice and provide rapid and site specific protection.
Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis. (102.9)
Authors: Parameswaran Neetha , Matsui Ken , Gupta Neetu 
Published: January 2023

Abstract
B cell chemotaxis occurs in response to specific chemokine gradients and is critical for homeostasis and immune response. The molecular regulation of B cell membrane-actin interactions during migration is poorly understood. In this study we report a role for ezrin, a member of the membrane-cytoskeleton crosslinking Ezrin-Radixin-Moesin (ERM) proteins, in the regulation of the earliest steps of B cell polarization and chemotaxis. We visualized chemokine-induced changes in murine B cell morphology using scanning electron microscopy, and spatiotemporal dynamics of ezrin in B cells using epifluorescence and total internal reflection microscopy. Upon chemokine stimulation ezrin is transiently dephosphorylated to assume an inactive conformation, and localizes to the lamellipodia. B cells expressing a phosphomimetic conformationally active mutant of ezrin, or those in which ezrin dephosphorylation was pharmacologically inhibited displayed impaired microvillar dynamics, morphological polarization and chemotaxis. Our data suggest a two-fold involvement of ezrin in B cell migration whereby it first undergoes chemokine-induced dephosphorylation to facilitate membrane flexibility, followed by relocalization to the actin-rich lamellipodia for dynamic forward protrusion of the cells.
Antigen-specific effector CD8 T-cells inhibit allergic responses via IFN-gamma secretion and dendritic cell interaction (103.4)
Authors: Tang Yafang , Chua Benson , Guan Shou Ping , Zhou Sophie , Ho Adrian , Wong Kenneth , Wong Kok Loon , Wong Fred , Kemeny David 
Published: January 2023

Abstract
Allergic inflammation of the airways causes changes in the lung wall that lead to inflammatory diseases such as asthma. Using a mouse model this response can be divided into an induction phase and an effector phase. Previously we have shown that transfer of CD8 T cells inhibits the induction of Th2 responses. In this study we have investigated the effect of CD8 T cells on the effector phase of the inflammatory lung response. In vitro activated OT-I CD8 T cells were transferred to ovalbumin (OVA)-alum immunized mice one day before challenge with OVA. Eosinophil infiltration and mucus secretion were inhibited by transfer of CD8 T cells. When OT-IxIFN-gamma-/-T cells were transferred, the inhibitory effect was abolished, suggesting an important role for IFN-gamma. In fact, without IFN-gamma, effector CD8 T cells were able to induce asthma-like inflammation which further proved the importance of IFN-gamma in the suppression of type II inflammation. We also investigated the effect of CD8 T cells on lung dendritic cell (DC) function. CD11c+CD11b+CD103- DCs from CD8 transferred mice increased largely in number and when co-cultured with CD4 T cells, they were able to induce more IFN-gamma production. These results suggest that in addition to regulating the induction of the allergic immune response, CD8 T cells can subsequently divert the local lung environment to one that favors Th1 immunity, through IFN-gamma and CD8-DC interaction.
Age-associated alterations of lipid metabolism and oxidative stress in the murine thymus are attenuated by in vivo growth hormone administration (104.13)
Authors: Mello-Coelho Valeria , Cutler Roy , Tammara Anita , Bunbury Allyson , Mattson Mark , Taub Dennis 
Published: January 2023

Abstract
The mechanisms by which GH facilitates the recovery of thymopoiesis during age-associated thymic atrophy are unknown. Herein, we analyzed the age-related lipid alterations in total thymus and thymocyte preparations derived from 04 to 18 month-old mice, and in thymi of GH-treated aged mice. Electrospray tandem mass spectrometry permitted us to detect increased amounts of tryglicerides (TG), free-cholesterol and C24:1 sphingomyelin in the total thymus of old mice as compared to those of young. Moreover, we verified a decrease in the sulfatide C24:1 and in unknown long-chain ceramides, and an increase in 4-HNE and 8-epi-prostaglandin F2α (PGF) in the thymi of older animals. Using immunohistochemistry, we verified an increase in the expression of TNFα and CD204 within the aged thymus sections. In analyzing thymocytes, we found a decrease in TG, free cholesterol and in sphingomyelin species with age. Interestingly, we detected a significant amount of ceramide C24:1 in thymocytes derived from old mice but not young. Following GH treatment, we observed a significant decrease in TG, free-cholesterol and PGF in the thymus of older animals. GH treatment significantly increased the amount of dihydroceramides and promoted a trend to decrease 4-HNE levels compared to thymi of age-matched denatured GH-treated control mice. These results suggest that increased oxidative stress associated with perturbed lipid metabolism within aged thymus can be attenuated after GH treatment.
Role for p53 in activation-induced cell death of T cell-independent B cell clones (104.16)
Authors: Mongini Patricia , Lee Hyunjoo , Nieto Jennifer , Chiorazzi Nicholas 
Published: January 2023

Abstract
B cell immunity involves clonal proliferation, differentiation of selected progeny into memory/effector cells, and activation-induced cell death (AICD) of others. Clonal expansion and contraction occur in human B2 cell cultures activated by surrogate C3dg-Ag and IL-4 ± BAFF (J Immunol 175:6143). The mechanism was here studied. Pro- and anti-apoptotic proteins were assessed by immunoblotting prior(d3-4) or during (d5-6) AICD and by immunostaining CFSE-labeled cells. Evidence of lesser Bim but elevated p53 and downstream proteins suggested p53-mediated apoptosis, perhaps triggered by expressed activation-induced cytosine deaminase (AID) (J Immunol 185:5300). This was reinforced by findings that AICD is reduced (but not ablated) by p53 siRNA or genetic deficiency in p53 or AID, in similarly activated mouse cells. A significant drop in Bcl-2 in dividing blasts preceded AICD and its importance was substantiated by greater clonal burst size in Bcl-2 TG-cultures. In germinal centers (GC), p53 is repressed by Bcl-6, resulting in infrequent p53 mutations in GC lymphomas (Phan et al., Nature 432:635). Our study suggests that B cell tumors with a higher incidence of p53 mutations may arise from inflamed peripheral tissues. In the latter, recirculating B cells will encounter C3dg-coated microbes or apoptotic cells and IL-4 and BAFF from innate immune system cells. The latter milieu would foster T cell-independent B cell growth and encourage positive selection of p53 mutants.
Mechanisms of thymic recovery and T cell reconstitution following sublethal ionizing radiation (104.21)
Authors: Këpuska Zana , Sempowski Gregory 
Published: January 2023

Abstract
Proper thymic function is important for maintaining lifelong peripheral homeostasis of naïve and memory T cells. Age-induced thymic involution is chronic and does not recover. Acute thymus involution in settings of stress can spontaneously recover. The goal of this research was to define mechanisms of thymic damage and recovery following acute stress (irradiation). Young and old BALB/c mice were sublethaly irradiated (≤ 125 rad).Thymus function was monitored by thymus weight, cellularity, and TCR gene re-arrangement (mTREC). In young, irradiation significantly reduced thymocyte number and depleted mTREC levels by day 7, followed by full recovery (day 42). In old, radiation did not cause further decrease in thymocyte number or mTREC compared to that induced by age. To define mechanisms of thymic involution/recovery expression of thymostimulatory factors and indicators of healthy thymus were analyzed.While IL-7 and FoxN1 mRNA levels were not impacted in the young, KGF and AIRE mRNA expression levels were significantly reduced during irradiation-induced involution. These levels restored to baseline 21 days prior to full thymus functional recovery. Thus, suggesting a critical role of thymic-stromal derived KGF in promoting stroma/thymocyte crosstalk to mediate thymus recovery. Overall, these findings may lead to a better understanding of mechanisms involved in thymus recovery from damage and inform development of strategies to restore thymic function in the aged.
Impact of aging on CD4 T cell helper functions (104.6)
Authors: Lefebvre Julie , Maue Alexander , Petell Ashlee , Lanthier Paula , Tighe Michael , Eaton Sheri , Haynes Laura 
Published: January 2023

Abstract
Impairment of the immune system in older people leads to increased susceptibility to infection and reduced antibody production following immunization. We have previously shown that intrinsic defects in CD4 T cell function occur in aged mice and that this negatively impacts the antibody response. In addition, other age-related changes can impact CD4 T cell priming. Using an adoptive transfer model, we show that the trafficking of young TCR Tg CD4 T cells to the T cell zones of secondary lymphoid organs is impaired when they are transferred into aged hosts compared to young hosts. This correlates with delayed expansion and reduced activation as measured by CFSE dilution and CD69 expression, respectively. Using immunofluorescent staining of spleen sections, we demonstrate that the structure of the B cell follicles and the expression of CCL21 are disorganized in aged hosts compared to young hosts, likely causing this reduced trafficking in aged hosts. This also likely contributes to the reduced induction of Tfh cells in the lymph nodes of aged mice. Finally, we found that fewer aged cells produce cytokines and that the pattern of cytokine production is also different, aged mice having more cells producing IL-17 but less cells producing IL-4, IL-10 and IFNγ than young mice. Thus, not only is the CD4 T cell response reduced with age, it is also qualitatively different which could account for reduced induction of protection following immunization.
Sensitivity of CD4+ effector memory T cells to Fas-induced apoptosis is due to increased localization of Fas to lipid raft microdomains (104.9)
Authors: Cruz Anthony , Ramaswamy Madhu , Siegel Richard 
Published: January 2023

Abstract
Fas-FasL interactions play a critical role in TCR-induced apoptosis of activated CD4+ T cells. Fas deficiency prompts accumulation of CD44+ memory T cells and autoimmunity in mice, suggesting Fas plays a role in memory and/or autoreactive T cell apoptosis. We have recently shown that CD4+ effector memory cells were sensitive to Fas-induced cell death, and also a correlation between lipid raft-associated Fas and sensitivity to apoptosis. A critical cysteine residue near the transmembrane helix of Fas has been shown to be responsible for its association with lipid rafts. Whether the lipid raft association of Fas is regulated in different primary cell types is not known. We have compared the post-translational modification state and membrane localization of Fas receptor in purified naïve versus memory human CD4+ T cells. Memory T cells have increased lipid raft-associated Fas receptor versus naïve cells, which could explain the increased Fas sensitivity in the memory pool. Using a competitive inhibitor to palmitoylation, we found the sensitivity of effector memory T cells to Fas-induced apoptosis depended on Fas palmitoylation. Utilizing click chemistry to analyze the palmitoylation state of Fas showed increased receptor palmitoylation in cells sensitive to Fas-mediated apoptosis compared to resistant cells. These results suggest post-translational palmitoylation and lipid raft localization of Fas as a regulatory mechanism in Fas-induced apoptosis in memory T cells.
Functionally impaired memory CD8 T cells are generated after vesicular stomatitis virus infection (105.13)
Authors: Obar Joshua , Zickovich Julianne , Meyer Susan , Yagita Hideo , Noelle Randolph 
Published: January 2023

Abstract
Intracellular pathogens are capable of inducing vigorous CD8 T cell responses. However, it is unclear whether all memory CD8 T cell populations are capable of providing robust protective immunity against secondary infection. While both vesicular stomatitis virus (VSV) and Listeria monocytogenes infection result in the generation of large memory CD8 T cell populations that are capable of rapid secondary expansion, only memory cells induced by L. monocytogenes were protective against secondary infection. The lack of protective immunity after VSV priming correlated with expression of PD-1 on memory CD8 T cells. Importantly, mAb blockade of PD-1 at the time of re-challenge enhanced the ability of the VSV-induced memory CD8 T cell population to provide protective immunity. Moreover, overt activation of CD40, but not TLR9, signaling during priming enables the memory CD8 T cell population to provide strong protective immunity. CD40 signaling appears to alter the programming of the CD8 T cell response induced by VSV infection. Our data demonstrate that not all vaccine vectors are equal in their ability to generate highly protective memory CD8 T cell populations, even though they may generate memory population capable of undergoing robust secondary expansion. Thus, understanding how the CD40 signaling pathways regulate the generation of highly protective memory CD8 T cells will provide key insights into memory CD8 T cell biology and vaccine development.
CD8-EOMEShigh T cells define a subpopulation of CD8 memory cells that restore CD127high expression after cART treatment in HIV infected patients. (105.27)
Authors: Hasley Rebecca , Hong Changwan , Le Saout Cecile , Kim Grace , Friesen Travis , Nakamura Yoriko , Park Jung-Hyun , Sneller Michael , Roby Gregg , Rehm Catherine , Lane Clifford , Catalfamo Marta 
Published: January 2023

Abstract
After acute viral infection a small population of effector CD8 T cells upregulate CD127 expression and develop into long lived resting memory T cells. During chronic infections, such as HIV, there is an accumulation of CD8 T cells with effector/memory-like phenotype. These observations led to the hypothesis that there is a developmental impairment in the long lived resting memory T cells within that setting. The transcription factors RUNX3 and Eomesodermin (EOMES) are important in the development of long lived memory CD8 T cells. We studied the dynamics of CD127 expression, RUNX3 and EOMES in patients with HIV infection and different levels of viremia. Consistent with other reports, CD127 expression was decreased in the memory CD8 T cell subset. The CD8 memory CD127low T cells showed increased expression of RUNX3 and EOMES mRNA, as well as effector molecules perforin and granzyme B. In patients with suppressed viremia, we could identify two populations of CD8 T cells expressing EOMEShigh and EOMESint. The EOMESint cells showed a short-lived effector phenotype (perforin+, granzyme B+, CD127low) and the EOMEShigh cells showed a memory-like phenotype (perforin-, CD127high). These results suggest that in human CD8 T cells, EOMES is necessary for the maintenance of long lived memory CD8 T cells and its expression was influenced by HIV-RNA levels and the associated inflammatory environment (R=0.4, p=0.01). These findings provide new insights into the pathogenesis of HIV infection.