bluuebunny/crossref_metadata_2025_split huggingface dataset:
Propagation and regulation of systemic autoimmunity by gammadelta T cells.
Authors: Peng S L , Madaio M P , Hayday A C , Craft J 
Published: December 2022

Abstract
Although many studies have demonstrated a pathogenic role for alphabeta T cells in murine lupus, little work has addressed gammadelta T cells. Here, the roles of alphabeta and gammadelta T cells in the pathogenesis of systemic autoimmunity were investigated by generating lupus-prone mice deficient in alphabeta T cells and/or gammadelta T cells. Mice deficient in gammadelta T cells developed an exacerbated disease phenotype compared with that of T cell-intact mice, consisting of augmented hypergammaglobulinemia and autoantibody production, more severe renal disease, and increased mortality, associated with a polyclonal expansion of conventional CD4+ alphabeta T cells. Conversely, alphabeta T cell-deficient animals developed a partial lupus syndrome, characterized by isotype-specific hypergammaglobulinemia, incompletely penetrant autoantibodies, and mild immune complex renal disease, all of which were driven by gammadelta T cell-dependent help. These data indicate that gammadelta T cells participate in both the regulation and the propagation of murine lupus.
Defective Rho GTPase regulation by IL-1 beta-converting enzyme-mediated cleavage of D4 GDP dissociation inhibitor.
Authors: Danley D E , Chuang T H , Bokoch G M 
Published: December 2022

Abstract
GTPases of the Rho family regulate many aspects of inflammatory cell activity, including motility, formation of toxic oxygen metabolites, and generation of proinflammatory cytokines. Defective regulation of such signaling pathways leads to a variety of acute and chronic inflammatory disorders, although the mechanisms by which this occurs have not been well defined. We describe in this work specific proteolytic cleavage of D4 GDI, a critical regulator of Rho GTPase activity in inflammatory leukocytes, by IL-1 beta-converting enzyme (ICE). Cleavage of D4 GDI by ICE occurs at Asp55, leading to the formation of the truncated D4 that is unable to effectively bind and regulate GTPases of the Rho family. Our data suggest that activation of ICE protease(s) at inflammatory sites leads to defective Rho GTPase regulation. Release of these critical regulatory proteins may contribute substantially to the inflammatory response at these sites, exacerbating and perpetuating the resulting tissue damage.
T cell regulation in adult transplantation tolerance.
Authors: Davies J D , Martin G , Phillips J , Marshall S E , Cobbold S P , Waldmann H 
Published: December 2022

Abstract
An encounter of the mature immune system with Ag usually leads to an immune response. If Ag is administered with CD4- and CD8-specific mAbs, the outcome of the response can be tolerance. This form of tolerance is peripheral, Ag specific, and maintained lifelong, and is associated with the suppression of nontolerant cells by CD4 cells of the tolerant host. Here we demonstrate that the degree of suppression is dependent on the number of suppressor cells. A neutralizing anti-IL-4 Ab was partially able to inhibit suppression, indicating a role for IL-4 in the regulation of Th1 rejection responses.
p70 S6 kinase sensitivity to rapamycin is eliminated by amino acid substitution of Thr229.
Authors: Sugiyama H , Papst P , Gelfand E W , Terada N 
Published: December 2022

Abstract
Rapamycin, which forms a complex with FK506-binding protein and FK506-binding protein-rapamycin-associated protein, induces immunosuppression through an as yet undefined pathway. Our previous studies demonstrated that rapamycin inactivates p7Os6k, which results in the inhibition of translation of ribosomal proteins. Here, we analyzed the mechanism of inactivation of p70s6k by rapamycin using site-directed mutagenesis of the phosphate acceptor site. We introduced a point mutation at Thr229 in the catalytic subdomain VIII of p7Os6k because Thr229 of p7Os6k corresponds to the phosphorylation site of mitogen-activated protein kinases by mitogen-activated protein kinase kinase and to the autophosphorylation site of protein kinase A whose phosphorylation is required for its full activation. Thr229 of rat p70s6k was substituted by either a neutral amino acid Ala (T229A) or by an acidic amino acid Glu (T229E). T229A-P70s6k, expressed in COS cells, migrated faster in SDS-polyacrylamide gels than wild-type p70s6k, and this mutation completely ablated the catalytic activity of the kinase. In contrast, T229E-p70s6k migrated more slowly in SDS-polyacrylamide gels, but demonstrated partial kinase activity (approximately 20% compared with the wild type). These data indicate that the negative charge at Thr229 which is normally achieved by phosphorylation of the residue, is important for the catalytic function of p70s6k. Further, the residual activity of T229E-p70s6k was not affected by rapamycin, implying that rapamycin-induced inactivation of p70s6k may be caused by dephosphorylation or impaired phosphorylation of Thr229.
Lack of association of secretory component with IgA in J chain-deficient mice.
Authors: Hendrickson B A , Rindisbacher L , Corthesy B , Kendall D , Waltz D A , Neutra M R , Seidman J G 
Published: December 2022

Abstract
J chain has been proposed to play a role in the mucosal transport of polymeric Igs (pIg) by the polymeric Ig receptor (pIgR). We have previously reported the generation of J chain-deficient mice. These mice exhibited elevated serum IgA and depleted biliary and fecal IgA levels compared with wild-type mice. We report here that, unlike the IgA levels in bile and feces, IgA levels in local mucosal and glandular secretions were not depressed in J chain-deficient mice. Breast milk, intestinal mucosal surface, and nasal wash IgA levels in the mutant mice were similar to wild-type mice while bronchoalveolar lavage IgA levels were higher in the J chain-deficient animals. Western blot analysis with an Ab to secretory component (SC), the portion of the pIgR that remains bound to pig in secretions, and immunoprecipitation with Abs directed against IgA showed that secreted IgA was associated with SC in wild-type but not J chain-deficient mice. The IgA in wild-type secretions was polymeric while the secretions of J chain-deficient mice contained IgA monomers and other nonpolymeric IgA forms. Thus, J chain is not essential for IgA transport by intestinal, mammary, or respiratory epithelia but is necessary for the stable association of pIgA with SC. Further, we suggest that J chain-deficient IgA is transported into secretions by a different mechanism than wild-type IgA.
Multiple HLA-A alleles can present an immunodominant peptide of the human melanoma antigen Melan-A/MART-1 to a peptide-specific HLA-A*0201+ cytotoxic T cell line.
Authors: Fleischhauer K , Tanzarella S , Wallny H J , Bordignon C , Traversari C 
Published: December 2022

Abstract
The majority of HLA-A*0201-restricted tumor-infiltrating lymphocytes from melanoma patients recognize a peptide, MT(27-35), derived from the Melan-A/MART-1 Ag. This study reports that six variants of HLA-A2 and the HLA-A28 subtype A*6901 can present peptide MT(27-35). A CTL line specific for peptide MT(27-35) was generated by in vitro stimulation of PBL of an HLA-A*0201+, healthy donor with peptide-pulsed, activated autologous B lymphoblasts. This CTL line was shown to recognize peptide MT(27-35) after endogenous processing on Melan-A/MART-1+/HLA-A2+ tumor cells. Moreover, a panel of B lymphoblastoid cell lines (BLCLs) expressing A*0202, A*0204, A*0205, A*0206, A*0209, and with lower efficiency A*6901, could be sensitized to lysis upon incubation with the relevant peptide. As demonstrated by the levels of ED50 and CD8 dependency of lysis, HLA-A*0204 and HLA-A*0205 presented the peptide as efficiently as HLA-A*0201, while the other four alleles were less efficient. Peptide-binding studies suggest that TCR- rather than peptide-binding affinity determines the T cell recognition levels of peptide-pulsed EBV-BLCLs expressing A*0201, A*0204, A*0206, and A*0209. Peptide-pulsed BLCLs expressing HLA-A*0207 or two additional subtypes of HLA-A28 were not recognized. MT(27-35)-specific CTL could also be raised from donors expressing HLA-A*0205. These findings have implications on the applicability of peptide vaccination with peptide MT(27-35) on melanoma patients.
Exacerbated viral hepatitis in IFN-gamma receptor-deficient mice is not suppressed by IL-12.
Authors: Schijns V E , Wierda C M , van Hoeij M , Horzinek M C 
Published: December 2022

Abstract
Both IL-12 and IFN-gamma have been implicated as principal inducers of type 1 immune responses required for the elimination of intracellular pathogens, such as viruses. We examined the in vivo antiviral role of both cytokines during coronavirus-induced hepatitis in a mouse hepatitis virus (MHV) model. The absence of IFN-gamma function in mice with a targeted disruption of the IFN-gamma R alpha-chain gene (IFN-gamma R -/-) resulted in increased susceptibility to coronaviral hepatitis associated with augmented viral replication and increased hepatocellular injury. The mutant mice showed a type 1 lymphokine response characterized by the normal high IFN-gamma and low IL-4 production. Unlike MHV-infected wild-type mice, however, the mutant IFN-gamma R -/- mice showed no increase in IL-12 p4O gene expression, similar to that in naive animals. IL-12 treatment failed to restore host resistance in IFN-gamma R -/- mice, but significantly protected MHV-susceptible C57BL/6 mice against lethal infection, although less than IFN-gamma treatment. Mice protected by IL-12 or IFN-gamma showed resistance against an otherwise lethal second MHV infection. Our data demonstrate that despite reduced IL-12 gene expression and defective IFN-gamma R function, virus-induced IFN-gamma production can occur. Furthermore, they emphasize the pivotal antiviral role of IFN-gamma in protection against acute coronavirus-induced hepatitis.
Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library.
Authors: Sahu A , Kay B K , Lambris J D 
Published: December 2022

Abstract
We have screened a phage-displayed random peptide library for binding to C3b, the proteolytically activated form of complement component C3, and have identified a novel peptide that suppresses complement activation. This phage-displayed peptide bound to C3, C3b, and C3c, but not to C3d, indicating that it binds to the C3c region of C3. A synthetic 27-amino acid peptide corresponding to the phage-displayed peptide also bound to C3 and C3 fragments and inhibited both the classical and alternative pathways of complement activation. The inhibition of complement activation was reversible. Studies with overlapping peptides indicated that the functional activity was located in the cyclic 13-amino acid N-terminal region (ICVVQDWGHHRCT) of the parent peptide. Reduction and alkylation of this 13-residue synthetic peptide destroyed its inhibitory activity. Analysis of the mechanism of inhibition revealed that the peptide inhibited C3 cleavage in normal human serum as well as when the alternative pathway was reconstituted with purified complement components, and the observed inhibition was not due to sterically hindered access to the C3a/C3b cleavage site. Further, the peptide did not inhibit the cleavage of factor B, indicating that it did not affect the interaction of CA with factor B or the formation of C3b,Bb. The peptide also had no effect on the binding of properdin to C3, demonstrating that the observed inhibition of C3 cleavage in normal human serum was not due in part to its effect on the properdin-stabilized C3 convertase, C3b,Bb,P. These results indicate that the peptide we have identified interacts with C3 to inhibit its activation.
Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis.
Authors: Agostini C , Trentin L , Facco M , Sancetta R , Cerutti A , Tassinari C , Cimarosto L , Adami F , Cipriani A , Zambello R , Semenzato G 
Published: December 2022

Abstract
Recent data suggest that the newly discovered cytokine IL-15 cooperates with IL-2 in driving T cell-mediated immune responses. The aim of this study was to determine the role of IL-15 in the regulatory networks leading to the development of T cell alveolitis in the lung of patients with sarcoidosis. We demonstrated that alveolar macrophages (AMs) isolated from the bronchoalveolar lavage of patients with active sarcoidosis expressed IL-15 mRNA and membrane and cytoplasmic IL-15, while AMs from healthy subjects and patients with inactive sarcoidosis did not. Pulmonary CD4+ T cells from sarcoid patients were equipped with the IL-2R subunits, which are able to bind IL-15, i.e., the IL-2R beta/IL-2R gamma complex, and proliferated in response to IL-15. Interestingly, the T cell proliferation elicited by IL-15 was comparable with that determined by IL-2. Following the addition of graded amounts of IL-15, IL-2-pulsed T cells showed a significant increase in their stimulation. TNF-alpha up-regulated the IL-15-mediated proliferative response of bronchoalveolar lavage T lymphocytes. Following the block of the IL-2R beta- and gamma-chains with specific mAbs, the stimulatory activity of IL-15 was abolished. The evaluation of the IL-2R on sarcoid AMs demonstrated the constitutive expression of alpha- and gamma-chain mRNA and proteins. Taken together, these findings demonstrate that IL-15 triggers the growth of sarcoid T cells through the IL-2R beta/IL-2R-gamma complex and raise the possibility that AMs may deliver proliferative signals for the development of the T cell alveolitis. Modulation of IL-2R on AMs could represent a critical variable in regulating local inflammatory responses.
IL-10 modulates formation of osteoclasts in murine hemopoietic cultures.
Authors: Owens J M , Gallagher A C , Chambers T J 
Published: December 2022

Abstract
IL-10, originally described as a cytokine synthesis inhibitory factor produced by T cells, has recently been found to suppress osteoblastic differentiation in mouse bone marrow cultures. Since osteoblastic cells exert a major influence on the production and regulation of osteoclasts, the cells that resorb bone, this suggests that the cytokine might play a role in the regulation of bone resorption. We, therefore, tested the actions of the cytokine on osteoclast formation and function. We found no effect of IL-10 on the resorptive function of mature osteoclasts, either when isolated or when incubated in the presence of osteoblastic cells. However, IL-10 suppressed bone resorption in bone marrow cultures and in cocultures of bone marrow stromal cell lines with hemopoietic spleen cells. In both systems, suppression of bone resorption was associated with a substantial reduction in the ratio of calcitonin receptor-positive cells to macrophages, suggesting that IL-10 exerts a reciprocal action on the differentiation of osteoclasts and macrophages from their shared precursor. This reciprocal action is very similar to that associated with the addition of macrophage CSF to hemopoietic cultures, and we found that IL-10 increased the expression of mRNA for macrophage CSF in bone marrow cultures. This potent inhibition of osteoclast formation by IL-10 suggests that IL-10 might play a role in the modulation of bone loss in inflammatory disorders.
Activation of the Na(+)/H(+) antiporter, Na+/HCO3(-)/CO3(2-) cotransporter, or Cl(-)/HCO3(-) exchanger in spontaneous thymocyte apoptosis.
Authors: Tsao N , Lei H Y 
Published: December 2022

Abstract
This study was undertaken to define the role of ion transporters on the apoptosis of thymocytes. Culture conditions, such as the ionic strength of NaCl, Ca2+, the buffer system (HCO3-/CO2), and the pH, could influence the spontaneous apoptosis of thymocytes. Depletion of NaCl in the culture medium either delayed or completely inhibited the apoptotic process of thymocytes, while its restoration led to a dose-dependent apoptosis. A high concentration (100 microM) of Ca2+ induced thymocyte apoptosis in the nominal absence of NaCl, whereas a low concentration (10 microM) enhanced apoptosis in the presence of 138 mM NaCl. Thymocytes had a higher spontaneous apoptotic rate in cultures without HCO3-/CO2 than in those with HCO3-/CO2. The thymocyte apoptosis completely ceased in medium at pH 6.0 and was considerably enhanced at pH 7.6. Intracellular pH, determined with the pH-sensitive bis-carboxyethyl carboxyfluorescein probe, was higher in apoptotic thymocytes than in nonapoptotic cells. Spontaneous apoptosis occurred in cells with alkaline intracellular condition, whereas it was considerably retarded in cells under acidified conditions. Amiloride analogue, including 5-(N,N-dimethyl)-amiloride (Na+/H+ antiporter), 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (Cl-/HCO3- exchanger), and 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid (Na+/HCO3-/CO3(2-) cotransporter), inhibited the spontaneous thymocyte apoptosis. In contrast, neither cycloheximide nor actinomycin D had the same effect. In addition, thymocyte apoptosis was enhanced by PMA, but inhibited by forskolin. Taken together, thymocytes cultured in vitro underwent apoptosis with increased intracellular pH via activation of Na+/H+ antiporter, Na+/HCO3-/CO3(2-) cotransporter, or Cl-/HCO3- exchanger. This process does not require de novo protein synthesis.
The production of macrophage inflammatory protein-1 alpha by human basophils.
Authors: Li H , Sim T C , Grant J A , Alam R 
Published: December 2022

Abstract
Macrophage inflammatory protein-1alpha (MIP-1alpha) has previously been shown to be produced by mononuclear cells, eosinophils, and neutrophils. Its production by basophils has not been investigated. The objective of this study was to investigate the production of MIP-1alpha by basophils. Peripheral blood basophils were separated by Percoll gradient centrifugation, cultured overnight, and processed for double immunocytochemistry using Abs against MIP-1alpha and FcepsilonRIalpha (alpha subunit of IgE receptor type 1). We demonstrated that basophils expressed immunoreactive MIP-1alpha upon stimulation with anti-IgE. Less than 5% of the basophils stained for MIP-1alpha without stimulation. The secretion of MIP-1alpha by basophils was studied by ELISA. In these experiments, basophils were further enriched to 65 to 99% (median, 86%) by a negative selection method. Basophils released MIP-1alpha when stimulated by Abs against IgE and FCepsilonRIalpha as well as IL-3 and the calcium ionophore, A23187. In parallel experiments, PBMC, eosinophils, and neutrophils did not produce MIP-1alpha in response to anti-IgE, but they did so in response to A23187. No MIP-1alpha release was detected in platelet preparations. Preincubation with IL-3 (15 min or 18 h) augmented anti-IgE-included basophil MIP-1alpha production. The secretion of MIP-1alpha by basophils was detectable shortly after stimulation and gradually increased over 24 h. Since MIP-1alpha has potent inflammatory and histamine-releasing activities, its production by basophils may indicate a positive feedback mechanism for allergic inflammation.
Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5.
Authors: Fuss I J , Neurath M , Boirivant M , Klein J S , de la Motte C , Strong S A , Fiocchi C , Strober W 
Published: December 2022

Abstract
In this study, we investigate whether human inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is associated with altered lymphokine secretion profiles, as recently found in various animal models of chronic intestinal inflammation. In initial studies, we determined the proliferative responses of purified lamina propria (LP) CD4+ T cells from patients with IBD under defined conditions of T cell stimulation. We found that IBD LP CD4+ T cells in comparison with control LP CD4+ T cells have diminished TCR/CD3 pathway proliferative responses, whereas CD2/CD28 accessory pathway proliferative responses are relatively preserved. In further studies centering on lymphokine production, we showed that LP T cells from inflamed Crohn's disease mucosa manifest increased IFN-gamma secretion compared with control LP T cells, particularly when stimulated via the CD2/CD28 pathway. Subsequent ELISPOT analysis indicated that this was due to an increased number of IFN-gamma-secreting CD4+ T cells. In contrast, IL-4 and IL-5 production by Crohn's disease LP T cells was decreased compared with that of control LP T cells. Of interest, IL-2 production by Crohn's disease LP T cells was also reduced, as was IL-2 production by peripheral blood T cells. In parallel studies, LP T cells from inflamed ulcerative colitis mucosa stimulated via either the TCR/CD3/CD28 or CD2/CD28 produced increased amounts of IL-5, again when measured either as secreted IL-5 or by ELISPOT analysis. Such increased IL-5 production was not associated with increased IL-4 secretion and, in contrast to Crohn's disease, ulcerative colitis LP T cell production of IL-2 and IFN-gamma was normal. Taken together, these studies provide strong evidence that the immunopathologic process characteristic of the two major forms of IBD is associated with very different cytokine secretion patterns. These different patterns may determine the type of inflammatory process present.
Costimulatory effects of T cell proliferation during infection with human T lymphotropic virus types I and II are mediated through CD80 and CD86 ligands.
Authors: Lal R B , Rudolph D L , Dezzutti C S , Linsley P S , Prince H E 
Published: December 2022

Abstract
The modulation of expression of CD80 and CD86 on T cells following infection with human T lymphotropic virus (HTLV)-I/II and its functional importance in T-T cell interactions was examined. Infection with HTLV-I/II leads to constitutive expression of CD80 and CD86, concomitant to down-modulation of CD28 on T cells. The CD80/CD86+ HTLV-infected T cells stimulated proliferation of allogeneic and autologous resting T cells, which could be specifically blocked by a soluble CTLA-4Ig chimeric protein, anti-CD80 or anti-CD86, but not by anti-CD54. It was necessary to inhibit interaction with both ligands (CD80 and CD86) to optimally block HTLV-mediated proliferation of allogeneic and autologous resting T cells. Simultaneous addition of anti-CD8O and anti-CD86 Abs also inhibited production of IFN-gamma, TNF-alpha, and IL-4, with no effect on IL-10 production, for both allo- and autologous T cell proliferation. Further, there was a direct correlation between the spontaneous proliferation of lymphocytes from patients infected with HTLV-II and expression of CD80, which could be blocked by simultaneous addition of anti-CD80 and anti-CD86. Taken together, these results suggest that HTLV-infected CD80/CD86+ T cells serve as APCs, leading to a sustained proliferation of T cells, and that both ligands participate in allostimulation, autologous proliferation, as well as spontaneous proliferation of HTLV-II-infected PBMC.