bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Responses Are Better Correlates of Vaccine Protection in the Elderly
Authors: McElhaney Janet E. , Xie Dongxu , Hager W. David , Barry Mary Beth , Wang Yazhen , Kleppinger Alison , Ewen Catherine , Kane Kevin P. , Bleackley R. Chris 
Published: April 2014

Abstract
It is commonly held that increased risk of influenza in the elderly is due to a decline in the Ab response to influenza vaccination. This study prospectively evaluated the relationship between the development of influenza illness, and serum Ab titers and ex vivo cellular immune responses to influenza vaccination in community dwelling older adults including those with congestive heart failure (CHF). Adults age 60 years and older (90 subjects), and 10 healthy young adult controls received the 2003-04 trivalent inactivated influenza vaccine. Laboratory diagnosed influenza (LDI) was documented in 9 of 90 older adults. Pre- and postvaccination Ab titers did not distinguish between subjects who would subsequently develop influenza illness (LDI subjects) and those who would not (non-LDI subjects). In contrast, PBMC restimulated ex vivo with live influenza virus preparations showed statistically significant differences between LDI and non-LDI subjects. The mean IFN-γ:IL-10 ratio in influenza A/H3N2-stimulated PBMC was 10-fold lower in LDI vs non-LDI subjects. Pre-and postvaccination granzyme B levels were significantly lower in CHF subjects with LDI compared with subjects without LDI. In non-CHF subjects with LDI, granzyme B levels increased to high levels at the time of influenza infection. In conclusion, measures of the ex vivo cellular immune response to influenza are correlated with protection against influenza while serum Ab responses may be limited as a sole measure of vaccine efficacy in older people. Ex vivo measures of the cell-mediated immune response should be incorporated into evaluation of new vaccines for older adults.
Cutting Edge: Novel Human Dendritic Cell- and Monocyte-Attracting Chemokine-Like Protein Identified by Fold Recognition Methods
Authors: Pisabarro M. Teresa , Leung Beatrice , Kwong Mandy , Corpuz Racquel , Frantz Gretchen D. , Chiang Nancy , Vandlen Richard , Diehl Lauri J. , Skelton Nicholas , Kim Hok Seon , Eaton Dan , Schmidt Kerstin N. 
Published: April 2014

Abstract
Chemokines play an important role in the immune system by regulating cell trafficking in homeostasis and inflammation. In this study, we report the identification and characterization of a novel cytokine-like protein, DMC (dendritic cell and monocyte chemokine-like protein), which attracts dendritic cells and monocytes. The key to the identification of this putative new chemokine was the application of threading techniques to its uncharacterized sequence. Based on our studies, DMC is predicted to have an IL-8-like chemokine fold and to be structurally and functionally related to CXCL8 and CXCL14. Consistent with our predictions, DMC induces migration of monocytes and immature dendritic cells. Expression studies show that DMC is constitutively expressed in lung, suggesting a potential role for DMC in recruiting monocytes and dendritic cells from blood into lung parenchyma.
Cutting Edge: Gut Microenvironment Promotes Differentiation of a Unique Memory CD8 T Cell Population
Authors: Masopust David , Vezys Vaiva , Wherry E. John , Barber Daniel L. , Ahmed Rafi 
Published: April 2014

Abstract
Whether tissue microenvironment influences memory CD8 T cell differentiation is unclear. We demonstrate that virus-specific intraepithelial lymphocytes in gut resemble neither central nor effector memory CD8 T cells isolated from spleen or blood. This unique phenotype arises in situ within the gut, suggesting that anatomic location plays an inductive role in the memory differentiation program. In support of this hypothesis, memory CD8 T cells changed phenotype upon change in location. After transfer and in vivo restimulation, gut or spleen memory cells proliferated, disseminated into spleen and gut, and adopted the memory T cell phenotype characteristic of their new environment. Our data suggests that anatomic location directly impacts the memory T cell differentiation program.
CD11b+/Gr-1+ Myeloid Suppressor Cells Cause T Cell Dysfunction after Traumatic Stress
Authors: Makarenkova Valeriya P. , Bansal Vishal , Matta Benjamin M. , Perez Lori Ann , Ochoa Juan B. 
Published: April 2014

Abstract
T cell dysfunction that occurs after surgery or trauma is associated with a poor clinical outcome. We describe that myeloid suppressor cells expressing CD11b+/Gr-1+ markers invade the spleen after traumatic stress and suppress T cell function through the production of arginase 1. We created a consistent model of traumatic stress in C57BL/6 mice to perform this work. A significant number of CD11b+/Gr-1+ cells expressing arginase 1 accumulated in T cell zones around the germinal centers of the white pulp of the spleen within 6 h of trauma and lasted for at least 72 h. Increased arginase activity and arginase 1 expression, along with increased [3H]arginine uptake, l-arginine depletion, and l-ornithine accumulation in the culture medium, were observed exclusively in CD11b+/Gr-1+ cells after traumatic stress. Flow cytometry revealed CD11b+/Gr-1+ as a heterogeneous myeloid suppressor cell also expressing low levels of MHC class I and II, CD80, CD86, CD31, and others. When compared with controls, trauma-induced CD11b+/Gr-1+ cells significantly inhibited CD3/CD28-mediated T cell proliferation, TCR ζ-chain expression, and IL-2 production. The suppressive effects by trauma CD11b+/Gr-1+ cells were overcome with the arginase antagonist N-hydroxy-nor-l-arginine or extrasupplementation of medium with l-arginine. Poor Ag-presenting capacity of control and trauma-induced CD11b+/Gr-1+ cells was detected in allogeneic murine leukocyte reaction. This study demonstrates that CD11b+/Gr-1+ cells invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism, probably that of arginine depletion. Understanding the mechanism of immune suppression by these cells has important clinical implications in the treatment of immune dysfunction after trauma or surgery.
P2X7 Receptors Regulate NKT Cells in Autoimmune Hepatitis
Authors: Kawamura Hiroki , Aswad Fred , Minagawa Masahiro , Govindarajan Sugantha , Dennert Gunther 
Published: April 2014

AbstractAdenine nucleotides induce danger signals in T cells via purinergic receptors, raising the question whether they exert similar effects on innate immunity. Here we show that micromolar concentrations of nicotinamide adenine dinucleotide (NAD) induce a rapid increase of annexin V staining in NKT cells in vitro, a response that requires expression of P2X7Rs. Consistent with this result, treatment of mice with NAD causes a temporary decrease of NKT cells in the liver and protects from Con A- and α-galactosylceramide-induced hepatitis, both of which require functional NKT cells. Resistance to liver injury is associated with decreased cytokine production by NKT cells in NAD-treated mice. In contrast, when NAD is injected into Con A- or α-galactosylceramide-primed mice, liver injury is exacerbated and cytokine production by NKT cells is increased. This effect is caused by P2X7R-mediated stimulation of activated NKT cells. In agreement, mice lacking P2X7Rs on lymphocytes suffer reduced liver injury, and animals lacking ADP-ribosyltransferase, the enzyme that uses NAD to attach ADP-ribosyl groups to cell surfaces, are also resistant to Con A-induced hepatitis. These results prompt the conclusion that engagement of P2X7Rs on NKT cells inhibits naive, while stimulating activated cells, resulting in suppression or stimulation of autoimmune hepatitis.
Developmental Alterations in Thymocyte Sensitivity Are Actively Regulated by MHC Class II Expression in the Thymic Medulla
Authors: Eck Steven C. , Zhu Peimin , Pepper Marion , Bensinger Steven J. , Freedman Bruce D. , Laufer Terri M. 
Published: April 2014

Abstract
Developing thymocytes are positively selected if they respond to self-MHC-peptide complexes, yet mature T cells are not activated by those same self-complexes. To avoid autoimmunity, positive selection must be followed by a period of maturation when the cellular response to TCR signals is altered. The mechanisms that mediate this postselection developmental tuning remain largely unknown. Specifically, it is unknown whether developmental tuning is a preprogrammed outcome of positive selection or if it is sensitive to ongoing interactions between the thymocyte and the thymic stroma. We probed the requirement for MHC class II-TCR interactions in postselection maturation by studying single positive (SP) CD4 thymocytes from K14/Aβb mice, in which CD4 T cells cannot interact with MHC class II in the thymic medulla. We report here that SP CD4 thymocytes must receive MHC class II signals to avoid hyperactive responses to TCR signals. This hyperactivity correlates with decreased expression of CD5; however, developmental tuning can occur independently of CD5, correlating instead with differences in the distribution of Lck. Thus, the maturation of postselection SP CD4 thymocytes is an active process mediated by ongoing interactions between the T cell and MHC class II molecules. This represents a novel mechanism by which the thymic medulla prevents autoreactivity.
CCL5 Modulates Pneumococcal Immunity and Carriage
Authors: Palaniappan Ravichandran , Singh Shailesh , Singh Udai P. , Singh Rajesh , Ades Edwin W. , Briles David E. , Hollingshead Susan K. , Royal Walter , Sampson Jacquelyn S. , Stiles Jonathan K. , Taub Dennis D. , Lillard James W. 
Published: April 2014

AbstractUnderstanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Recently, it has been shown that genetic polymorphisms can result in diminished expression of CCL5, which results in increased susceptibility to and progression of infectious diseases. We show that CCL5, together with Th cytokine mRNA expression, is temporally up-regulated during pneumococcal carriage. To determine the contribution of CCL5 to pneumococcal surface antigen A-specific humoral and cellular pneumococcal immunity, mice were treated with anti-CCL5 or control Abs before and during Streptococcus pneumoniae strain EF3030-challenge for the initiation of carriage. CCL5 blockade resulted in a decrease of CD4+ and CD8+ T cells as well as CD11b+ cells in the spleen, cervical lymph node, lung, and nasopharyngeal associated lymphoid tissue during the recognition phase of the pneumococcal adaptive immune response. CCL5 blockade significantly reduced the Ag-specific IgG2a and IgG1 Abs in serum and IgA Ab levels in nasal washes. These decreases also corresponded to reductions in Ag-specific T cell (mucosal and systemic) responses. CCL5 inhibition resulted in decreasing the quantity of IL-4- and IFN-γ-secreting CD4+ T cells and increasing the number of Ag-specific IL-10-producing CD4+ T cells; these changes combined also corresponded with the transition from pneumococcal carriage to lethal pneumonia. These data suggest that CCL5 is an essential factor for the induction and maintenance of protective pneumococcal immunity.
B Cell-Specific Deficiency for Smad2 In Vivo Leads to Defects in TGF-β-Directed IgA Switching and Changes in B Cell Fate
Authors: Klein Jörg , Ju Wenjun , Heyer Jörg , Wittek Britta , Haneke Torsten , Knaus Petra , Kucherlapati Raju , Böttinger Erwin P. , Nitschke Lars , Kneitz Burkhard 
Published: April 2014

AbstractSmad2 is a member of the intracellular mediators that transduce signals from TGF-β receptors and activin receptors. Targeted inactivation of Smad2 in mice leads to early lethality before gastrulation. It was shown previously that TGF-βRII deficiency in vivo leads to defects in B cell homeostasis, Ag responsiveness, and IgA class switch recombination of B cells. To investigate the importance of Smad2-mediated signaling in B lymphocytes, we generated a B cell-specific inactivation of Smad2 in mice (bSmad2−/−). bSmad2−/− mice had normal B cell numbers in the spleen but showed a reduced population of marginal zone B cells. In contrast, B cells in Peyer’s patches and peritoneal B-1a cells of bSmad2−/− mice were increased in numbers. bSmad2−/− mice showed a reduced number of surface-IgA+ B cells and of IgA-secreting cells in Peyer’s patches, decreased levels of IgA in serum, and, after immunization with a T cell-dependent Ag, a reduced IgA response. Class switch recombination to IgA was impaired in Smad2-deficient B cells, when stimulated in vitro with LPS in the presence of TGF-β. The growth-inhibitory effects of TGF-β in LPS-stimulated B cells were not affected in Smad2-deficient B cells. In summary, our data indicate a crucial role of Smad2 in mediating signals for the TGF-β-directed class switch to IgA and the induction of IgA responses in vivo. Other B cell functions like growth-inhibitory signaling, which are known to be regulated by signals via the TGF-βR, are not affected in Smad2-deficient B cells.
CD161 (Human NKR-P1A) Signaling in NK Cells Involves the Activation of Acid Sphingomyelinase
Authors: Pozo David , Valés-Gómez Mar , Mavaddat Nasim , Williamson Sharon C. , Chisholm Susan E. , Reyburn Hugh 
Published: April 2014

Abstract
NK and NKT cells play a major role in both innate immunity and in influencing the development of adaptive immune responses. CD161 (human NKR-P1A), a protein encoded in the NK gene complex, is a major phenotypic marker of both these cell types and is thought to be involved in the regulation of NK and NKT cell function. However, the mechanisms of action and signaling pathways of CD161 are poorly understood. To identify molecules able to interact with the cytoplasmic tail of human CD161 (NKR-P1A), we have conducted a yeast two-hybrid screen and identified acid sphingomyelinase as a novel intracellular signaling pathway linked to CD161. mAb-mediated cross-linking of CD161, in both transfectants and primary human NK cells, triggers the activation of acid, but not neutral sphingomyelinase. The sphingomyelinases represent the catabolic pathway for N-acyl-sphingosine (ceramide) generation, an emerging second messenger with key roles in the induction of apoptosis, proliferation, and differentiation. These data therefore define a novel signal transduction pathway for the CD161 (NKR-P1A) receptor and provide fresh insights into NK and NKT cell biology.
Functional Hierarchy of the N-Terminal Tyrosines of SLP-76
Authors: Jordan Martha S. , Sadler Jeffrey , Austin Jessica E. , Finkelstein Lisa D. , Singer Andrew L. , Schwartzberg Pamela L. , Koretzky Gary A. 
Published: April 2014

Abstract
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a central role in T cell activation and T cell development. SLP-76 has three functional modules: an acidic domain with three key tyrosines, a central proline-rich domain, and a C-terminal Src homology 2 domain. Of these, mutation of the three N-terminal tyrosines (Y112, Y128, and Y145) results in the most profound effects on T cell development and function. Y112 and Y128 associate with Vav and Nck, two proteins shown to be important for TCR-induced phosphorylation of proximal signaling substrates, Ca2+ flux, and actin reorganization. Y145 has been shown to be important for optimal association of SLP-76 with inducible tyrosine kinase, a key regulator of T cell function. To investigate further the role of the phosphorylatable tyrosines of SLP-76 in TCR signaling, cell lines and primary T cells expressing SLP-76 with mutations in individual or paired tyrosine residues were analyzed. These studies show that Tyr145 of SLP-76 is the most critical tyrosine for both T cell function in vitro and T cell development in vivo.
Modulation of the TLR-Mediated Inflammatory Response by the Endogenous Human Host Defense Peptide LL-37
Authors: Mookherjee Neeloffer , Brown Kelly L. , Bowdish Dawn M. E. , Doria Silvana , Falsafi Reza , Hokamp Karsten , Roche Fiona M. , Mu Ruixia , Doho Gregory H. , Pistolic Jelena , Powers Jon-Paul , Bryan Jenny , Brinkman Fiona S. L. , Hancock Robert E. W. 
Published: April 2014

Abstract
The sole human cathelicidin peptide, LL-37, has been demonstrated to protect animals against endotoxemia/sepsis. Low, physiological concentrations of LL-37 (≤1 μg/ml) were able to modulate inflammatory responses by inhibiting the release of the proinflammatory cytokine TNF-α in LPS-stimulated human monocytic cells. Microarray studies established a temporal transcriptional profile and identified differentially expressed genes in LPS-stimulated monocytes in the presence or absence of LL-37. LL-37 significantly inhibited the expression of specific proinflammatory genes up-regulated by NF-κB in the presence of LPS, including NFκB1 (p105/p50) and TNF-α-induced protein 2 (TNFAIP2). In contrast, LL-37 did not significantly inhibit LPS-induced genes that antagonize inflammation, such as TNF-α-induced protein 3 (TNFAIP3) and the NF-κB inhibitor, NFκBIA, or certain chemokine genes that are classically considered proinflammatory. Nuclear translocation, in LPS-treated cells, of the NF-κB subunits p50 and p65 was reduced ≥50% in the presence of LL-37, demonstrating that the peptide altered gene expression in part by acting directly on the TLR-to-NF-κB pathway. LL-37 almost completely prevented the release of TNF-α and other cytokines by human PBMC following stimulation with LPS and other TLR2/4 and TLR9 agonists, but not with cytokines TNF-α or IL-1β. Biochemical and inhibitor studies were consistent with a model whereby LL-37 modulated the inflammatory response to LPS/endotoxin and other agonists of TLR by a complex mechanism involving multiple points of intervention. We propose that the natural human host defense peptide LL-37 plays roles in the delicate balancing of inflammatory responses in homeostasis as well as in combating sepsis induced by certain TLR agonists.
Transepithelial Pathogen Uptake into the Small Intestinal Lamina Propria
Authors: Vallon-Eberhard Alexandra , Landsman Limor , Yogev Nir , Verrier Bernard , Jung Steffen 
Published: April 2014

Abstract
The lamina propria that underlies and stabilizes the gut lining epithelium is densely populated with strategically located mononuclear phagocytes. Collectively, these lamina propria macrophages and dendritic cells (DC) are believed to be crucial for tissue homeostasis as well as the innate and adaptive host defense. Lamina propria DC were recently shown to gain direct access to the intestinal lumen by virtue of epithelium-penetrating dendrites. However, the role of these structures in pathogen uptake remains under debate. In this study, we report that entry of a noninvasive model pathogen (Aspergillus fumigatus conidia) into the murine small intestinal lamina propria persists in the absence of either transepithelial dendrites or lamina propria DC and macrophages. Our results suggest the existence of multiple pathogen entry pathways and point at the importance of villus M cells in the uptake of gut lumen Ags. Interestingly, transepithelial dendrites seem altogether absent from the small intestine of BALB/c mice suggesting that the function of lamina propria DC extensions resides in their potential selectivity for luminal Ags, rather than in general uptake or gut homeostasis.
Cutting Edge: IL-4-Induced Protection of CD4+CD25− Th Cells from CD4+CD25+ Regulatory T Cell-Mediated Suppression
Authors: Pace Luigia , Rizzo Stefania , Palombi Cecilia , Brombacher Frank , Doria Gino 
Published: April 2014

Abstract
CD4+CD25+ T regulatory (Treg) cells are a CD4+ T cell subset involved in the control of the immune response. In vitro, murine CD4+CD25+ Treg cells inhibit CD4+CD25− Th cell proliferation induced by anti-CD3 mAb in the presence of APCs. The addition of IL-4 to cocultured cells inhibits CD4+CD25+ Treg cell-mediated suppression. Since all cell types used in the coculture express the IL-4Rα chain, we used different combinations of CD4+CD25− Th cells, CD4+CD25+ Treg cells, and APCs from wild-type IL-4Rα+/+ or knockout IL-4Rα−/− mice. Results show that the engagement of the IL-4Rα chain on CD4+CD25− Th cells renders these cells resistant to suppression. Moreover, the addition of IL-4 promotes proliferation of IL-4Rα+/+CD4+CD25+ Treg cells, which preserve full suppressive competence. These findings support an essential role of IL-4 signaling for CD4+CD25− Th cell activation and indicate that IL-4-induced proliferation of CD4+CD25+ Treg cells is compatible with their suppressive activity.
Dominant Tolerance to Kidney Allografts Induced by Anti-Donor MHC Class II Antibodies: Cooperation between T and Non-T CD103+ Cells
Authors: Degauque Nicolas , Lair David , Dupont Alexandre , Moreau Anne , Roussey Gwénaelle , Moizant Frédérique , Hubert François Xavier , Louvet Cédric , Hill Marcelo , Haspot Fabienne , Josien Régis , Usal Claire , Vanhove Bernard , Soulillou Jean Paul , Brouard Sophie 
Published: April 2014

Abstract
Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection. The kidney grafts of tolerant animals display an accumulation of TCR Cβ, FoxP3, and IDO transcripts. Moreover, as compared with syngeneic recipients, tolerant recipients harbor a large infiltrate of MHC class II+ cells and CD103+ cells. In vitro, splenocytes from tolerant recipients exhibit decreased donor-specific proliferation, which is restored by depletion of non-T cells and partially restored by the blockade of IDO. Finally, splenocytes from tolerant recipients, but not purified T cell splenocytes, transfer donor-specific infectious tolerance without chronic rejection, after infusion into naive recipients, over two generations. However, splenocytes depleted of T cells or splenocytes depleted of CD103+ cells fail to transfer tolerance. Collectively, these data show that a single administration of anti-donor MHC class II alloimmune serum induces a tolerant state characterized by an infiltration of the kidney graft by regulatory T cells and CD103+ cells. These data also show that the transfer of tolerance requires the presence of both T cells and CD103+ dendritic cells. The precise mechanism of cooperation of these two cell subsets remains to be defined.
Downstream of Tyrosine Kinases-1 and Src Homology 2-Containing Inositol 5′-Phosphatase Are Required for Regulation of CD4+CD25+ T Cell Development
Authors: Kashiwada Masaki , Cattoretti Giorgio , McKeag Lisa , Rouse Todd , Showalter Brian M. , Al-Alem Umaima , Niki Masaru , Pandolfi Pier Paolo , Field Elizabeth H. , Rothman Paul B. 
Published: April 2014

Abstract
The adaptor protein, downstream of tyrosine kinases-1 (Dok-1), and the phosphatase SHIP are both tyrosine phosphorylated in response to T cell stimulation. However, a function for these molecules in T cell development has not been defined. To clarify the role of Dok-1 and SHIP in T cell development in vivo, we compared the T cell phenotype of wild-type, Dok-1 knockout (KO), SHIP KO, and Dok-1/SHIP double-knockout (DKO) mice. Dok-1/SHIP DKO mice were runted and had a shorter life span compared with either Dok-1 KO or SHIP KO mice. Thymocyte numbers from Dok-1/SHIP DKO mice were reduced by 90%. Surface expression of both CD25 and CD69 was elevated on freshly isolated splenic CD4+ T cells from SHIP KO and Dok-1/SHIP DKO, suggesting these cells were constitutively activated. However, these T cells did not proliferate or produce IL-2 after stimulation. Interestingly, the CD4+ T cells from SHIP KO and Dok-1/SHIP DKO mice produced higher levels of TGF-β, expressed Foxp3, and inhibited IL-2 production by CD3-stimulated CD4+CD25− T cells in vitro. These findings suggest Dok-1 and SHIP function in pathways that influence regulatory T cell development.