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T Cell Mediated Antibody lnvariance in an Immune Response Against A Bacterial Carbohydrate Antigen Requires CD28/B7–1 Costimulation  [PDF]
André Rademaekers,Eckehart K lsch,Christoph Specht
Clinical and Developmental Immunology , 2001, DOI: 10.1155/2001/87168
Abstract: The humoral immune response against α(1→3) dextran (Dex) in BALB/c mice is characterized by the formation of predominantly IgM antibodies bearing the J558 idiotype. IgG antibodies do not appear in euthymic mice. In athymic animals however, the response proceeds to a vigorous IgG production. In euthymic mice formation of IgG is suppressed by J558 idiotype- specific regulatory T cells recognizing in association with I-Ed and in cognate T/B interaction the VH CDR3 derived peptide of the J558 idiotpye. Only B-2 lymphocytes produce IgG whereas B-1 cells do not participate in the production of this Ig class. Using a novel synthetic all α(1→3)-D-gluco configurated tetrasaccharide the Dex-specific B cells can for the first time be analyzed in FACS. In experiments using this newly designed low molecular Dex no signs of B cell apoptosis can be found. This demonstrates a true silencing of persisting Bγ memory cells and supports previous by adoptive transfer experiments. In this suppression an involvement of CD28/B7–1 interaction can be demonstrated which is a necessary costimulatory suppression signal in addition to the cognate TCR/peptide-I-Ed interaction between J558 Id-specific T cells and J558 idiotype beating B cells. This results in an activation of 178–4 Ts cells, leading to an overall suppression of the Dex-specific IgG isotype production on the one hand and on the other hand provides a signal for the survival and clonal expansion of J558 Id-positive B cells.
The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis
Andrzej Pawlik, Lidia Ostanek, Iwona Brzosko, Marek Brzosko, Marek Masiuk, Boguslaw Machalinski, Barbara Gawronska-Szklarz
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar766
Abstract: T-cell-mediated autoimmune responses are considered to play a role in the pathogenesis of rheumatoid arthritis (RA) [1]. Activation of T lymphocytes requires two signals from antigen-presenting cells. The first signal, the binding of the T-cell receptor to its antigen major histocompatibility complex ligand, provides specificity of antigens. The second signal is mediated by costimulatory molecules, of which a family of proteins called B7 appears to be the most potent. The B7 costimulatory pathway involves at least two molecules, B7-1 (CD80) and B7-2 (CD86), on antigen-presenting cells, both of which can interact with their counter-receptors, CD28 and CTLA-4, on T cells [2]. The interaction of the CD28 receptor on the lymphocyte with receptors of the B7 family on the antigen-presenting cell is one of the most important of these costimulatory pathways. This signal induces T-cell activations and clonal expansion and inhibits T-cell apoptosis. Activation of the T-cell receptor without costimulation of the CD28 receptor does not induce activation but instead induces anergy or cell death [3]. Recent studies have shown that patients with RA carry a subset of CD4+ T cells – CD4+CD28- T cells – that lacks the receptor CD28. Cells of this CD4+CD28- subset have several features differentiating them from classic T helper cells. They do not depend on the B7/CD28 pathway for activation, do not express the CD80 receptor, are incapable of activating B cells, have significant cytolytic activity, and express high levels of IFN-γ and IL-2 [4]. Thus, the presence of significant numbers of CD4+CD28- T cells could shift immune response from B-cell activation and production of immunoglobulins toward activation of type-1 T helper cells and production of IFN-γ and involvement of macrophages releasing matrix-degrading proteases. CD4+CD28- T cells are infrequent in healthy individuals (comprising 0.1–2.5% of T cells) [5], whereas higher levels have been seen in patients with unstable angina,
B7/CD28 in Central Tolerance: Costimulation Promotes Maturation of Regulatory T Cell Precursors and Prevents Their Clonal Deletion  [PDF]
Maria Hinterberger,Ludger Klein
Frontiers in Immunology , 2011, DOI: 10.3389/fimmu.2011.00030
Abstract: According to the “two-step model,” the intrathymic generation of CD4+ regulatory T (Treg) cells segregates into a first, T cell receptor (TCR)-driven phase and a second, cytokine-dependent phase. The initial TCR stimulus gives rise to a CD25+Foxp3? developmental intermediate. These precursors subsequently require cytokine signaling to establish the mature CD25+Foxp3+ Treg cell phenotype. In addition, costimulation via CD28/B7 (CD80/86) axis is important for the generation of a Treg cell repertoire of normal size. Recent data suggest that CD28 or B7 deficient mice lack CD25+Foxp3? Treg cell progenitors. However, these data leave open whether costimulation is also required at subsequent stages of Treg differentiation. Also, the fate of “presumptive” Treg cells carrying a permissive TCR specificity in the absence of costimulation remains to be established. Here, we have used a previously described TCR transgenic model of agonist-driven Treg differentiation in order to address these issues. Intrathymic adoptive transfer of Treg precursors indicated that costimulation is dispensable once the intermediate CD25+Foxp3? stage has been reached. Furthermore, lack of costimulation led to the physical loss of presumptive Treg cells rather than their escape from central tolerance and differentiation into the conventional CD4+ T cell lineage. Our findings suggest that CD28 signaling does not primarily operate through enhancing the TCR signal strength in order to pass the threshold intensity required to initiate Treg cell specification. Instead, costimulation seems to deliver unique and qualitatively distinct signals that coordinately foster the developmental progression of Treg precursors and prevent their negative selection.
Role of Dendritic Cell Maturity/Costimulation for Generation, Homeostasis, and Suppressive Activity of Regulatory T Cells  [PDF]
Manfred B. Lutz
Frontiers in Immunology , 2011, DOI: 10.3389/fimmu.2011.00039
Abstract: Tolerogenicity of dendritic cells (DCs) has initially been attributed exclusively to immature/resting stages, while mature/activated DCs were considered strictly immunogenic. Later, all different subsets among the myeloid/conventional DCs and plasmacytoid DCs have been shown to bear tolerogenic potential, so that tolerogenicity could not be attributed to a specific subset. Immunosuppressive treatments of immature DC subsets could prevent re-programming into mature DCs or upregulated inhibitory surface markers or cytokines. Furthermore, the different T cell tolerance mechanisms anergy, deletion, immune deviation, and suppression require different quantities and qualities of costimulation by DCs. Since expansion of regulatory T cells (Tregs) has been shown to be promoted best by fully mature DCs the role of CD80/B7-1 and CD86/B7-2 as major costimulatory molecules for Treg biology is under debate. In this review, we discuss the role of these and other costimulatory molecules on myeloid DCs and their ligands CD28 and CD152/CTLA-4 on Tregs for peripheral conversion from naive CD4+ T cells into the major subsets of Foxp3+ Tregs and Foxp3? IL-10+ regulatory type-1 T cells (Tr1) or Tr1-like cells and their role for peripheral maintenance in the steady state and after activation.
The MAP Kinases are Differently Utilized by CD28 and CD2 Adhesion Pathways in Superantigen-Activated Jurkat T cells
Biological Research , 2003, DOI: 10.4067/S0716-97602003000200016
Abstract: to mimic the two-signal requirements for t cell activation mediated by ligands, we exposed the superantigens sea or see (signal 1) to t cells incubated with hla-dr/lfa-3 or hla-dr/b7-1-cho transfected cells (signal 2). lfa-3 costimulation was able to induce t cell proliferation as well as ifn-g and il-4 production at similar levels as in cells induced by b7-1. analysis of the cd28re of the il-2 promoter showed specific transcription factor recruitment at the cd28re element upon induction by b7-1/see. further functional studies with an il-2 enhancer-promoter carrying either wild type or mutated versions of the cd28re site revealed that this element is necessary for full activation upon b7-1 costimulation. while both cd28/b7-1 and cd2/lfa-3 costimulation resulted in the up-regulation of il-4 and ifn-g promoters, il-2 promoter activity and production of il-2 were only seen after b7-1 costimulation. however, contrary to what has been previously proposed, we show that costimulation with either b7-1 or lfa-3 further enhanced the erk-2 activity and strongly activated the p38 mapk pathway, but only b7-1 costimulation induced high levels of jnk-1 activity. these data suggest that the differential effect of cd28 vs. cd2 can be related to the difference in the ability of the two pathways to induce jnk-1 activity.
The MAP Kinases are Differently Utilized by CD28 and CD2 Adhesion Pathways in Superantigen-Activated Jurkat T cells
Biological Research , 2003,
Abstract: To mimic the two-signal requirements for T cell activation mediated by ligands, we exposed the superantigens SEA or SEE (signal 1) to T cells incubated with HLA-DR/LFA-3 or HLA-DR/B7-1-CHO transfected cells (signal 2). LFA-3 costimulation was able to induce T cell proliferation as well as IFN-g and IL-4 production at similar levels as in cells induced by B7-1. Analysis of the CD28RE of the IL-2 promoter showed specific transcription factor recruitment at the CD28RE element upon induction by B7-1/SEE. Further functional studies with an IL-2 enhancer-promoter carrying either wild type or mutated versions of the CD28RE site revealed that this element is necessary for full activation upon B7-1 costimulation. While both CD28/B7-1 and CD2/LFA-3 costimulation resulted in the up-regulation of IL-4 and IFN-g promoters, IL-2 promoter activity and production of IL-2 were only seen after B7-1 costimulation. However, contrary to what has been previously proposed, we show that costimulation with either B7-1 or LFA-3 further enhanced the ERK-2 activity and strongly activated the p38 MAPK pathway, but only B7-1 costimulation induced high levels of JNK-1 activity. These data suggest that the differential effect of CD28 vs. CD2 can be related to the difference in the ability of the two pathways to induce JNK-1 activity.
CD28: Direct and Critical Receptor for Superantigen Toxins  [PDF]
Raymond Kaempfer,Gila Arad,Revital Levy,Dalia Hillman,Iris Nasie,Ziv Rotfogel
Toxins , 2013, DOI: 10.3390/toxins5091531
Abstract: Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to elicit an inflammatory cytokine storm and lethality, superantigens must bind directly to CD28. Blocking access of the superantigen to its CD28 receptor with peptides mimicking the contact domains in either toxin or CD28 suffices to protect mice effectively from lethal shock. Our finding that CD28 is a direct receptor of superantigen toxins broadens the scope of microbial pathogen recognition mechanisms.
Evidence Implicating the Ras Pathway in Multiple CD28 Costimulatory Functions in CD4+ T Cells  [PDF]
Sujit V. Janardhan, Kesavannair Praveen, Reinhard Marks, Thomas F. Gajewski
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024931
Abstract: CD28 costimulation is a critical event in the full activation of CD4+ T cells that augments cytokine gene transcription, promotes cytokine mRNA stability, prevents induction of anergy, increases cellular metabolism, and increases cell survival. However, despite extensive biochemical analysis of the signaling events downstream of CD28, molecular pathways sufficient to functionally replace the diverse aspects of CD28-mediated costimulation in normal T cells have not been identified. Ras/MAPK signaling is a critical pathway downstream of T cell receptor stimulation, but its role in CD28-mediated costimulation has been controversial. We observed that physiologic CD28 costimulation caused a relocalization of the RasGEF RasGRP to the T cell-APC interface by confocal microscopy. In whole cell biochemical analysis, CD28 cross-linking with either anti-CD28 antibody or B7.1-Ig augmented TCR-induced Ras activation. To determine whether Ras signaling was sufficient to functionally mimic CD28 costimulation, we utilized an adenoviral vector encoding constitutively active H-Ras (61L) to transduce normal, Coxsackie-Adenovirus Receptor (CAR) transgenic CD4+ T cells. Like costimulation via CD28, active Ras induced AKT, JNK and ERK phosphorylation. In addition, constitutive Ras signaling mimicked the ability of CD28 to costimulate IL-2 protein secretion, prevent anergy induction, increase glucose uptake, and promote cell survival. Importantly, we also found that active Ras mimicked the mechanism by which CD28 costimulates IL-2 production: by increasing IL-2 gene transcription, and promoting IL-2 mRNA stability. Finally, active Ras was able to induce IL-2 production when combined with ionomycin stimulation in a MEK-1-dependent fashion. Our results are consistent with a central role for Ras signaling in CD28-mediated costimulation.
Targeting CD28, CTLA-4 and PD-L1 Costimulation Differentially Controls Immune Synapses and Function of Human Regulatory and Conventional T-Cells  [PDF]
Nahzli Dilek, Nicolas Poirier, Philippe Hulin, Flora Coulon, Caroline Mary, Simon Ville, Henri Vie, Béatrice Clémenceau, Gilles Blancho, Bernard Vanhove
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083139
Abstract: CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs). What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff) but inhibition of suppression by regulatory T cells (Tregs), while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.
Inducible Deletion of CD28 Prior to Secondary Nippostrongylus brasiliensis Infection Impairs Worm Expulsion and Recall of Protective Memory CD4+ T Cell Responses  [PDF]
Hlumani Ndlovu,Mathew Darby,Monika Froelich,William Horsnell,Fred Lühder,Thomas Hünig,Frank Brombacher
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003906
Abstract: IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28?/? mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28?/loxCre+/?+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28?/? mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28?/loxCre+/? mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28?/? mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28?/? mice and tamoxifen treated CD28?/loxCre+/? mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28?/loxCre+/? mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection.
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