bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71).
Authors: Chirmule N , McCloskey T W , Hu R , Kalyanaraman V S , Pahwa S 
Published: January 2023

Abstract
One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.
Autoantibodies against beta-crystallins induce lens epithelial cell damage and cataract formation in mice.
Authors: Singh D P , Guru S C , Kikuchi T , Abe T , Shinohara T 
Published: January 2023

Abstract
One-year-old B6C3/f mice, injected with beta-crystallins emulsified with CFA, developed lens epithelial cell damage. Both serum transfer and mAb transfer studies clearly established that the autoimmune insult is induced by humoral immunity. Older mice were more susceptible to autoimmune insult than younger animals. Lens epithelial cell damage invariably proceeded to cortical and posterior subcapsular cataract formation. This mouse model of experimental autoimmune cataract formation will facilitate the exploration of the relation between immune phenomena and human age-related cataract.
Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene immunization.
Authors: Mendoza R B , Cantwell M J , Kipps T J 
Published: January 2023

Abstract
Interaction of CD40 with its ligand (CD154) can induce CD40-bearing APCs to express immune stimulatory accessory molecules that facilitate immune recognition. We evaluated whether a plasmid vector encoding CD154 (pCD40L) could influence the immune response to a transgene protein encoded by coinjected plasmid DNA. We found that coinjection of pCD40L in BALB/c mice enhanced the Ab response to beta-galactosidase induced by i.m. or intradermal injection of placZ, a plasmid DNA vector encoding beta-galactosidase. Furthermore, i.m. or intradermal coinjection of pCD40L with placZ enhanced the generation of CTL specific for P815 cells transfected with placZ. This study indicates that pCD40L can serve as a genetic adjuvant capable of augmenting humoral and cellular immune responses to Ags encoded by plasmid DNA expression vectors.
Resting B cells from autoimmune lupus-prone New Zealand Black and (New Zealand Black x New Zealand White)F1 mice are hyper-responsive to T cell-derived stimuli.
Authors: Jongstra-Bilen J , Vukusic B , Boras K , Wither J E 
Published: January 2023

Abstract
To determine whether B cells from New Zealand Black (NZB) and (New Zealand Black x New Zealand White)F1 (NZB/W) mice possess intrinsic defects that lead to altered immune responsiveness, we purified resting B cells from these mice and compared their surface phenotype and function with those of resting B cells isolated from BALB/c and DBA/2 nonautoimmune mouse strains. Flow cytometric analysis of freshly isolated resting B cells revealed that NZB and NZB/W resting B cells are conventional B2-type cells similar to their nonautoimmune counterparts. Despite this, resting B cells from young NZB and NZB/W mice express lower levels of CD23 on their surface and aberrant levels of intracellular IgM. Upon stimulation, resting B cells from young NZB and NZB/W mice demonstrate increased proliferation, IgM secretion, or enhanced expression of costimulatory molecules in response to a variety of different T cell-derived stimuli, including cytokines and signals generated through CD40. Therefore, B cell hyper-responsiveness to T cell stimuli is immunodominant or codominant in NZB/W mice. Taken together, our results suggest that intrinsic B cell hyper-responsiveness may play a role in the pathogenesis of autoimmune disease in NZB and NZB/W mice. The increased clonal expansion of these B cells together with increased Ig production and enhanced costimulatory capacity serve to amplify the immune response. In the context of normal but incomplete T cell tolerance, B cell hyperresponsiveness to the limited signals provided by partially tolerant T cells may be sufficient to yield an autoantibody response.
TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T cell analog containing a unique Th0 subpopulation.
Authors: Prussin C , Foster B 
Published: January 2023

Abstract
Murine NK1 natural T (NT) cells are a population of alphabeta T cells that express NK cell receptors and an invariant TCR rearrangement. These cells rapidly produce large amounts of IL-4 upon activation and have been suggested to promote Th2 differentiation. We sought to determine whether a human NK1 T cell analogue could be detected in PBMC, and if so, characterize the TCR usage, cytokine expression, and surface phenotype of this subset. Using flow cytometry, we have demonstrated a distinct population of V alpha24+, V beta11+, CD56+ T cells consistent with NT cells. Upon sequencing, these cells expressed an invariant V alpha24-J alphaQ TCR rearrangement, verifying their identity as a human NK1 T cell analogue. NT cells demonstrated increased frequencies of both IFN-gamma and IL-4 production. Strikingly, 30 to 45% of CD4+ NT cells expressed IL-4, a sixfold greater frequency than that seen in mainstream CD4+ alphabeta T cells. Contrary to the pattern seen with mainstream T cells, virtually all IL-4-producing NT cells coexpressed IFN-gamma, indicating that this subset of NT cells has a unique Th0 phenotype. These data establish that V alpha24+ NT cells are a potent source of IL-4 and as such, may play a role in Th2 priming in human immune responses. This work demonstrates that human NT cells can be phenotypically identified and functionally studied in the blood of healthy or diseased subjects.
Single amino acid mutations in the murine MHC class II A beta cytoplasmic domain abrogate antigen presentation.
Authors: Laufer T M , Smiley S T , Ranger A , Clements V K , Ostrand-Rosenberg S , Glimcher L H 
Published: January 2023

Abstract
Class II MHC molecules are heterodimeric transmembrane glycoproteins that function in the presentation of Ag to CD4+ T cells. Deletion of the cytoplasmic domains of the murine class II A alpha- and A beta-chains has previously been shown to diminish Ag presentation and abrogate rejection of class II-transfected tumor cells. To examine the contributions of individual amino acid residues of the A beta cytoplasmic domain to Ag presentation and tumor rejection, we have produced a series of cell lines expressing A beta class II molecules with site-directed mutations. An A beta(k) cDNA was constructed with mutations in the five conserved amino acid residues, Q224, K225, L235, L236, and Q237 (delta5). In addition, cDNA were produced in which alanine was individually substituted for A beta(k) cytoplasmic domain residues 224 through 237 or doubly substituted at residues G226 and P227 or L235 and L236. These mutant cDNAs were individually cotransfected with wild-type A alpha cDNA into the class II-negative M12.C3 B lymphoma and Sal sarcoma cell lines. As was previously reported for transfectants lacking the entire A beta(k) cytoplasmic domain, the delta5 M12.C3 transfectant could not effectively present Ag to an autoreactive Ak-restricted T cell hybrid, and the delta5 Sal transfectant was not rejected when inoculated into syngeneic hosts. A finer analysis revealed that alteration of the individual residue Q224 or the two residues G226 and P227 abrogated Ag presentation in vitro, while mutation of G226 diminished tumor rejection in vivo. Thus, the function of the A beta cytoplasmic domain in Ag presentation both in vitro and in vivo can be disturbed by mutation of single amino acid residues.
Role for IL-15/IL-15 receptor beta-chain in natural killer 1.1+ T cell receptor-alpha beta+ cell development.
Authors: Ohteki T , Ho S , Suzuki H , Mak T W , Ohashi P S 
Published: January 2023

Abstract
Mouse TCR alphabeta+ cells expressing NKR-P1 (NK1+ T cells in the C57BL/6 strain) are classified as a unique subset that require beta2m-associated, MHC class I-like molecules for development and preferentially express particular V beta and V alphaJ domains of the TCR. We show here that NK1+ T cells express the IL-2R beta/IL-15R beta that is normally present on conventional NK cells, but not T cells. In mice lacking IL-2R beta/IL-15R beta chain, the number of NK1+ T cells is dramatically reduced. However, in IL-2-deficient mice, NK1+ T cells develop normally. Moreover, NK1+ T cells proliferate upon stimulation by IL-15, and the proliferation is blocked by the addition of anti-IL-2R beta/IL-15R beta Abs. Collectively, our data indicate that NK1+ T cells require IL-2R beta/IL-15R beta chain in an IL-2-independent manner and demonstrate that IL-15 plays a crucial role during development.
Maternal immunization with a soluble TCR-Ig chimeric protein: long term, V beta-8 family-specific suppression of T cells by maternally transferred antibodies.
Authors: McKeever U , Khandekar S , Jesson M , Newcomb J , Gregory P , Naylor J , Haskins K , Jones B 
Published: January 2023

Abstract
Maternal transfer of TCR clonotypic Ab protected young NOD mice against the adoptive transfer of diabetes by the BDC 2.5 T cell clone. The effect of maternal anti-TCR Vbeta-8 Ab on T cell development and function has now been investigated. SJL/J mice, which lack TCR Vbeta-8, were immunized with soluble, chimeric D10 TCR-IgG1 containing Vbeta-8.2. The (SJL/J x AKR/J) F1 offspring of immunized female SJL/J mice were severely depleted of peripheral T cells bearing Vbeta-8 until 11 to 17 wk of age. The loss of Vbeta-8 expression did not appear to be due to modulation of cell surface TCR. Since the Vbeta-8+ T cell population was unperturbed in the (AKR/J x SJL/J) F1 offspring of D10 TCR-IgG1-immunized AKR/J mothers making D10 clonotypic Ab, the effect was immunologically specific. The deletion of Vbeta-8+ T cells had functional consequences. In the in vitro response to the superantigen, staphylococcal enterotoxin B, the usually observed participation of Vbeta-8.2+ T cells was largely suppressed, whereas the recruitment of Vbeta-3+ T cells remained unaltered. In control mice, T cell responses to the 134- to 146-residue peptide of conalbumin (pCA(134-146)) were biased toward use of Valpha-2/Vbeta-8.2 TCR. In D10 TCR-IgG1 maternally immunized (SJL x AKR/J) F1 mice, the T cell responses to pCA(134-146) were suppressed, and T cell lines derived from these in vitro were devoid of Vbeta-8.2 expression. With an increased understanding of TCR V gene usage in autoimmune diseases, similar strategies for the depletion of autoreactive T cells may become feasible in humans.
CD40 and IL-4 regulate murine CD27L expression.
Authors: Hartwig U F , Karlsson L , Peterson P A , Webb S R 
Published: January 2023

Abstract
It is well known that interactions between accessory molecules on T cells and their ligands on APC play a key role in regulating T cell effector activity. The factors controlling the expression of these molecules are thus important determinants in the outcome of T cell activation. We have examined the expression of the murine ligand for CD27, a costimulatory molecule on T cells. Evidence is shown that CD27L is expressed at a low level on resting B cells but not on T cells, and that activation of B cells by culture with LPS or anti-IgM Ab increases the expression of CD27L. Interestingly, coligation of CD40 down-regulates CD27L on LPS-activated B cells but not on anti-Ig-activated cells. These findings suggest that costimulation via the CD27-CD27L pathway may be limited to interactions involving Ag-specific B cells, i.e., B cells specifically activated via their Ig receptors. In addition, testing a spectrum of different cytokines indicated that IL-4 and TGF, but not IL-2, IL-10, or IFN-gamma, prevented up-regulation of CD27L expression on activated B cells even when activation was induced by Ig signaling. The capacity of IL-4 to prevent CD27L expression could thus serve to limit CD27-CD27L interactions to Th1-type T cell responses.
Independent regulation of cutaneous lymphocyte-associated antigen expression and cytokine synthesis phenotype during human CD4+ memory T cell differentiation.
Authors: Teraki Y , Picker L J 
Published: January 2023

Abstract
Although considerable attention has been paid to the development of cytokine synthesis heterogeneity during memory T cell differentiation, little information is available on how this function is coregulated with homing receptor expression. The development of skin-homing, CD4+ memory T cells in the human provides an excellent model for such investigation, since 1) the skin supports both Th1- and Th2-predominant responses in different settings, and 2) the skin-homing capability of human memory T cells correlates with and appears to depend on expression of the skin-selective homing receptor cutaneous lymphocyte-associated Ag (CLA). In this study, we used multiparameter FACS analysis to examine expression of CLA vs IFN-gamma, IL-4, and IL-2 synthesis capabilities among fresh peripheral blood CD4+ memory T cells, and Th1 vs Th2 memory T cells generated in vitro from purified CD4+ naive precursors by cyclic activation in polarizing culture conditions. Among normal peripheral blood T cells, CLA expression was essentially identical among the IFN-gamma- vs IL-4-producing CD4+ memory subsets, clearly indicating the existence of in vivo mechanisms capable of producing both Th1 vs Th2 skin-homing T cells. In vitro differentiation of naive CD4+ T cells confirmed the independent regulation of CLA and all three cytokines examined, regulation that allowed differential production of IFN-gamma-, IL-4-, and IL-2-producing, CLA+ memory subsets. These studies also 1) demonstrated differences in regulatory factor activity depending on the differentiation status of the responding cell, and 2) revealed CLA expression to be much more rapidly reversible on established memory cells than cytokine synthesis capabilities.
Cytokine induction of the ability of human monocyte CD44 to bind hyaluronan is mediated primarily by TNF-alpha and is inhibited by IL-4 and IL-13.
Authors: Levesque M C , Haynes B F 
Published: January 2023

Abstract
Ligation of CD44 by hyaluronan (HA) is a key proinflammatory event that regulates lymphocyte and monocyte adhesion and cytokine production. While most immune cells express CD44, few immune cells constitutively bind HA. We have previously shown that monocyte CD44 acquires the ability to bind HA after in vitro culture of PBMC in human serum and, therefore, we have investigated a series of human cytokines and bacterial LPS for their ability to induce and/or inhibit monocyte CD44 to bind HA. We found that IL-1alpha, IL-1beta, IL-3, granulocyte macrophage (GM)-CSF, and TNF-alpha, as well as bacterial LPS, all directly induced peripheral blood monocytes to bind HA. In contrast, IL-2 and IL-15 up-regulated monocyte CD44 HA-binding in PBMC suspensions, but not in purified monocyte suspensions. An anti-TNF-alpha-neutralizing Ab inhibited IL-1alpha-, IL-1beta-, IL-3-, and GM-CSF-mediated monocyte HA binding. In addition, treatment of IL-2- and IL-15-stimulated PBMC cultures with an anti-TNF-alpha Ab prevented IL-2- and IL-15-induced monocyte HA binding, thus identifying TNF-alpha as a lymphocyte-derived factor that acted on monocytes to induce HA binding. In contrast, IL-4 and IL-13 were potent inhibitors of monocyte CD44-HA binding induced by either human serum or by IL-1alpha, IL-1beta, IL-3, GM-CSF, or TNF-alpha. IL-10 had dual effects on monocyte CD44-HA binding. Alone, IL-10 induced HA binding to PBMC monocyte CD44, while in contrast, IL-10 inhibited IL-1-induced monocyte CD44 binding to HA. Taken together, these studies identify a network of T cell and monocyte-derived cytokines that regulate HA binding to peripheral blood monocyte CD44, primarily through TNF-alpha.
Extracellular ATP and UTP control the generation of reactive oxygen intermediates in human macrophages through the opening of a charybdotoxin-sensitive Ca2+-dependent K+ channel.
Authors: Schmid-Antomarchi H , Schmid-Alliana A , Romey G , Ventura M A , Breittmayer V , Millet M A , Husson H , Moghrabi B , Lazdunski M , Rossi B 
Published: January 2023

Abstract
Human monocyte-derived macrophages possess a NADPH oxidase that catalyzes superoxide formation upon phagocytosis. Extracellular ATP per se does not activate NADPH oxidase but potentiates superoxide generation triggered by opsonized zymosan. UTP can substitute for ATP with the same efficiency, suggesting that ATP mediates its effects specifically through P2U receptors. Extracellular UTP stimulates a rapid increase in cytoplasmic Ca2+ concentration in monocytic cells, which results from a release of intracellular Ca2+ stores. Moreover, UTP-induced calcium increase is sufficient to activate a charybdotoxin-sensitive Ca2+-dependent outward K+ channel (K(Ca)). The activity of this channel develops between 0.1 and 1.0 microM free cytoplasmic Ca2+ concentration; it is half-blocked by 10 nM charybdotoxin but insensitive to iberiotoxin. Under asymmetrical K+ conditions, this K(Ca) channel does not depend on membrane potential and is characterized by a linear single-current voltage relationship in the voltage range of -100 to +50 mV, giving a unitary conductance of 10 pico-Siemens. Interestingly, ATP/UTP-induced oxygen radicals release was inhibited by charybdotoxin in the same range of concentration as the UTP-induced K(Ca) channel. Furthermore, we show that ATP or UTP fail to enhance oxygen radicals production before K(Ca) channel is expressed (3 days). The electrogenic nature of the NADPH oxidase, i.e., its level of activation, being dependent on the plasmic membrane potential, might provide the causal link between the reactive oxygen intermediates generation and the opening of the K(Ca) channel.
Identification and characterization of a novel beta chemokine containing six conserved cysteines.
Authors: Hedrick J A , Zlotnik A 
Published: January 2023

Abstract
The chemokines are emerging as a diverse and expanding family of cytokines. In this study, we report the identification of a novel beta (CC) chemokine that exhibits an unusual pattern of six conserved cysteines and was thus designated 6Ckine. The primary amino acid sequence of 6Ckine is highly conserved in humans, mice, and pigs and contains the expected four cysteines characteristic of the beta chemokine family plus two additional carboxyl-terminal cysteines. Expression of human 6Ckine appears to be restricted to lymphoid organs, particularly lymph node, spleen, and appendix, while murine 6Ckine has a broader tissue distribution with the highest mRNA levels found in spleen and lung. Recombinant murine 6Ckine was chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils. Together these data demonstrate that 6Ckine is a novel member of the chemokine superfamily.
Degenerate and promiscuous recognition by CTL of peptides presented by the MHC class I A3-like superfamily: implications for vaccine development.
Authors: Threlkeld S C , Wentworth P A , Kalams S A , Wilkes B M , Ruhl D J , Keogh E , Sidney J , Southwood S , Walker B D , Sette A 
Published: January 2023

Abstract
Recent data demonstrate that HLA class I alleles can be grouped into superfamilies based on similarities of their peptide-binding motifs. In this study, we have tested the immunogenicity and antigenicity of peptides capable of degenerate binding to multiple HLA class I molecules of the A3-like superfamily. The assay systems utilized included both primary in vitro cultures of lymphocytes from healthy donors, as well as in vitro restimulation of lymphocytes from HIV-infected individuals. Several of the peptides capable of binding more than one HLA A3-like class I molecule were also found to be immunogenic in the context of this same group of A3-like molecules (degenerate CTL recognition). Furthermore, some of the CTL lines thus generated demonstrated promiscuous recognition of the cognate epitope in the context of MHC molecules from more than one member of the superfamily. The fine Ag specificity of this phenomenon was further analyzed using two promiscuous CTL clones derived from A3 and A11 individuals, respectively, and specific for an epitope in the HIV-1 reverse transcriptase. By the use of single-amino acid-substitution analogues, it was demonstrated that the fine specificity of the TCR is largely maintained between MHC-matched and MHC-mismatched presentation of peptide within the A3-like superfamily. These results indicate that the similar peptide-binding specificities among different members of the A3-like superfamily can be reflected in a remarkable similarity in the peptide-MHC complex structures engaged by the TCR and responsible for T cell activation.
Augmentation of mature CD4+ T cell responses to isolated antigenic class II proteins by fibronectin and intercellular adhesion molecule-1.
Authors: Brunmark A , O'Rourke A M 
Published: January 2023

Abstract
Mature CD4+ T cells can undergo stable adhesion to isolated antigenic MHC complexes, and upon TCR engagement exhibit up-regulated adhesion to the integrin ligands fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1). Here, we have examined T cell responses to purified antigenic class II complexes, alone or coimmobilized in the presence of FN or ICAM-1. T cell adhesion to immobilized peptide-MHC complexes alone stimulated suboptimal, but marked levels of IFN-gamma and IL-2 secretion, and this was accompanied by cell proliferation. T cell adhesion to both FN and ICAM-1 strongly augmented cytokine release and T cell proliferation. Activation of Vbeta3+ and Vbeta8+ T cell lines by isolated staphylococcal enterotoxin-MHC complexes was also examined, and surprisingly, a Vbeta8+ T cell line displayed significant cell adhesion or later response to staphylococcal enterotoxin B-MHC complexes only when Ag was coimmobilized with ICAM-1 or FN. The results demonstrate that adhesion of CD4+ T cells to ICAM-1 or FN activated by natural TCR ligands can strongly augment T cell signaling and downstream responses. Moreover, for some Ags, T cell interaction with accessory ligands may be critical in attaining a threshold level of receptor occupancy for cell activation.