In vivo MAb anti-mouse CD28 (2023)

in vitroStimulation/activation of T cells
Lacher, S.M., et al. (2018). "NF-kappaB-inducing kinase (NIK) is a key posttranscriptional regulator of T-cell activation that affects F-actin dynamics and TCR signaling" J Autoimmune 94:110-121.PubMed

NF-kappaB-inducing kinase (NIK) is a key protein of the non-canonical NF-kappaB signaling pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T-cells using T-cell-specific NIK-deficient (NIK(DeltaT)) mice. Although NIK(DeltaT) mice showed normal development of lymphatic organs, they were resistant to induction of CNS autoimmunity. T-cells from NIK(DeltaT) mice did not have a delayed initial response, could not enhance T-bet and migrate to the CNS. Proteome analysis of activated NIK(-/-) T cells revealed deregulated expression of proteins involved in immune synapse formation: particularly proteins involved in cytoskeleton dynamics. Consistent with this, we found that NIK-deficient T cells after TCR intervention were impaired in Zap70, LAT, AKT, ERK1/2 and PLCgamma phosphorylation. Therefore, our data reveal a previously unknown role of NIK in the preparation and differentiation of T cells.

in vitroStimulation/activation of T cells
Wendland, K. et al. (2018). "Retinoic acid signaling in thymic epithelial cells regulates thymopoiesis" J Immunol 201(2): 524-532.PubMed

Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals that regulate TEC differentiation and homeostasis are still not fully understood. In this study, we present the keyliveRole of the vitamin A metabolite retinoic acid (RA) in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and medullary TEC CD80(lo)MHC class II(lo) showed subset-specific changes in gene expression, which in cTEC included genes involved in proliferation, growth and epithelial differentiation. Mice whose TEC did not respond to RA showed increased proliferation of cTEC, accumulation of Ag-1(hi) cTEC stem cells, and in early life a reduction in the number of TEC in the bone marrow. These changes resulted in reduced thymic cellularity at an early age, reduced numbers of monopositive CD4 and CD8 in young and adult mice, and improved survival of peripheral CD8(+) T cells after TCR stimulation. Taken together, our results identify RA as a regulator of TEC homeostasis, essential for TEC function and normal thymogenesis.

in vitroStimulation/activation of T cells
Ron-Harel, Ν., et al. (2016). "Mitochondrial biogenesis and proteomic remodeling drive one-carbon metabolism for T-cell activation" Cell Metab 24(1): 104-117.PubMed

Stimulation of naïve T cells activates anabolic metabolism to promote the transition from quiescence to growth and proliferation. Here we show that naïve activation of CD4(+) T cells induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified extensive remodeling of the mitochondrial proteome during the first 24 h of T cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism being the most strongly induced pathway. Serine-driven salvage pathways and mitochondrial one-carbon metabolism contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 reduced T cell survival in culture and antigen-specific T cell abundancelive. During T cell activation, remodeling of the mitochondrial proteome creates specialized mitochondria with enhanced one-carbon metabolism critical for T cell activation and survival.

in vitroStimulation/activation of T cells
Gu, A.D., et al. (2015). "A critical role of the transcription factor Smad4 in T cell function that is independent of growth factor receptor beta signaling" Immunity 42(1): 68-79.PubMed

Transforming growth factor beta (TGF-beta) suppresses T cell function to maintain self-tolerance and promote tumor immune system evasion. However, it remains unclear how Smad4, a transcription factor component of TGF-beta signaling, regulates T cell function. Here we show that Smad4 plays a key role in promoting T cell function in autoimmunity and antitumor immunity. Deletion of Smad4 rescued lethal autoimmunity resulting from TGF-beta receptor (TGF-betaR) deletion and T cell-mediated tumor rejection. Although Smad4 was required for T-cell generation, homeostasis and effector function, once activated it was dispensable for T-cell proliferationin vitroIlive. The transcription factor Myc was found to mediate Smad4-controlled T cell proliferation. This study thus demonstrates a requirement for Smad4 for T cell-mediated autoimmunity and tumor rejection that goes beyond the current paradigm. It highlights a TGF-betaR-independent role of Smad4 in promoting T-cell function, autoimmunity, and antitumor immunity.

in vitroStimulation/activation of T cells
Choi, Y.S., et al. (2015). "LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6" Nat Immunol 16(9): 980-990.PubMed

Follicular helper T-cells (TFH-cells) are specialized effector CD4(+) T-cells that help B-cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate TFH cell differentiation have not yet been fully elucidated. Here, we report that selective loss of Lef1 or Tcf7 (encoding the transcription factor LEF-1 and TCF-1, respectively) resulted in TFH cell defects, while deletion of Lef1 and Tcf7 severely impaired TFH cell differentiation and GC formation. Forced expression of LEF-1 enhanced TFH differentiation. LEF-1 and TCF-1 coordinated this differentiation through two general mechanisms. First, they determined the response of naïve CD4(+) T cells to signals from TFH cells. Second, they promoted early TFH differentiation through a multidimensional approach of maintaining the expression of the cytokine receptors IL-6Ralpha and gp130, increasing the expression of the costimulatory receptor ICOS, and promoting the expression of the transcriptional repressor Bcl6.

in vitroStimulation/activation of T cells
Xu, H. et al. (2015). "Regulation of B cell bifurcation pathways by competition between transcription factors IRF4 and IRF8" Nat Immunol.PubMed

In antigen recognition, B cells carry out a bifurcated reaction in which some cells rapidly differentiate into plasmablasts, while others undergo affinity maturation into germinal centers (GCs). Here, we identified a double negative feedback loop between the transcription factors IRF4 and IRF8 that regulates the initial developmental division of activated B cells as well as the GC response. IRF8 reduced B-cell antigen receptor (BCR) signaling, facilitated antigen-specific interaction with helper T cells, and enhanced antibody affinity maturation, while antagonizing IRF4-driven plasmablast differentiation. Genome-wide analysis revealed concentration-dependent effects of IRF4 and IRF8 in the regulation of various gene expression programs. Stochastic modeling suggests that a double negative feedback loop is sufficient to cause the bifurcation of B cell developmental trajectories.

liveBlocked by CD28
Rouhani, S.J., et al. (2015). "The role of lymphatic endothelial cells expressing peripheral tissue antigens in the induction of CD4 T cell tolerance" Nat Commun 6:6771.PubMed

Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce tolerance to CD8 T-cell deletion. LECs express MHC-II molecules, suggesting that CD4 T cells can also tolerate them. We show that when beta-galactosidase (beta-gal) is expressed in LECs, beta-gal-specific CD8 T cells are cleared by the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous beta-gal associated with MHC-II molecules on beta-gal-specific CD4 T cells. The lack of presentation is independent of antigen localization since membrane-bound hemagglutinin and I-Ealpha are also not presented to MHC-II molecules. LECs express invariant chain and cathepsin L, but not H2-M, suggesting that they cannot load endogenous antigenic peptides onto MHC-II molecules. Importantly, LECs transport beta-gal to dendritic cells, which then present it to induce CD4 T-cell anergy. Therefore, LECs serve as an antigen reservoir for CD4 T cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T cell tolerance via LAG-3.

in vitroStimulation/activation of T cells
Rabenstein, H., et al. (2014). "Differential kinetics of antigen-dependent CD4+ and CD8+ T cells" J Immunol 192(8): 3507-3517.PubMed

Ag recognition by the TCR is essential for the expansion of specific T cells, which then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in their initial APCs and MHC ligands, we compared their Ag persistence requirements during their expansion phase side by side. Proliferation and effector differentiation of transgenic and polyclonal mouse TCR T cells were therefore analyzed for transient and sustained TCR signals. After equally strong stimulation, the proliferation of CD4+ T cells was dependent on the prolonged presence of Ag, while CD8+ T cells could divide and differentiate into effector cells despite cessation of Ag presentation. CD4+ T cell proliferation was not affected by Th lineage or memory differentiation, nor was it blocked by coinhibitory signaling or lack of inflammatory stimuli. Indeed, sustained proliferation of CD8+ T cells was independent of autopeptide/MHC-derived signals. Subgroup divergence is also illustrated by surprisingly large transcriptional differences, showing a greater propensity of CD8+ T cells for programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells in processing TCR signals for proliferation. We also found that MHC class II-restricted peptide presentation is more efficiently prolonged by activating dendritic cellsliveInstead of a class I imported one. In summary, our data show that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide after a much shorter TCR signal.

in vitroStimulation/activation of T cells
Xiao, N. et al. (2014). "The E3 ubiquitin ligase Itch is required for follicular T helper cell differentiation" Nat Immunol 15(7): 657-666.PubMed

Follicular T helper cells (T(FH) cells) are responsible for strong B cell-mediated immunity, and Bcl-6 is a central factor in T(FH) cell differentiation. However, the molecular mechanisms that regulate the induction of T(FH) cells remain unclear. Here, we found that E3 ubiquitin ligase is essential for T(FH) cell differentiation, germinal center responses, and immunoglobulin G (IgG) responses to acute viral infections. Pruritus acted intrinsically on CD4(+) T cells at early stages of T cell development (FH). Itch appears to precede Bcl-6 expression because Bcl-6 expression was significantly attenuated in Itch(-/-) cells and differentiation of Itch(-/-) T cells into T(FH)-cells was restored by forcing Bcl-6 expression . Pruritus is associated with the transcription factor Foxo1 and promotes its ubiquitination and degradation. Defective T(FH) differentiation of Itch(-/-) T cells is corrected by Foxo1 deletion. Therefore, our results suggest that itch acts as a major positive regulator of T(FH) cell differentiation.

in vitroStimulation/activation of T cells
Tang, W. et al. (2014). "Oncoprotein and transcriptional regulator Bcl-3 regulate plasticity and pathogenicity of autoimmune T cells" Immunity 41(4): 555-566.PubMed

Bcl-3 is an atypical member of the IkappaB family that regulates transcription in the nucleus through association with p50 (NF-kappaB1) or p52 (NF-kappaB2) homodimers. Despite evidence supporting the general physiological importance of Bcl-3, little is known about its cell-specific functions or mechanisms. Here we demonstrate a T cell intrinsic function of Bcl-3 in autoimmunity. Bcl-3-deficient T cells fail to induce disease in T cell transfer-induced colitis and experimental autoimmune encephalomyelitis. Protection from the disease was associated with a decrease in Th1 cells, which produced the cytokines IFN-gamma and GM-CSF, and an increase in Th17 cells. Although differentiation into Th1 cells was not affected in the absence of Bcl-3, differentiated Th1 cells were transformed into less pathogenic Th17-like cells, in part through mechanisms involving the expression of the transcription factor RORgammat. Therefore, Bcl-3 limited Th1 cell plasticity and promoted pathogenicity by blocking conversion to Th17-like cells, revealing a unique mode of regulation that modulates adaptive immunity.

in vitroStimulation/activation of T cells
Choi, Y.S., et al. (2013). "Bcl6-expressing CD4 follicular helper cells commit early and have memory-forming capacity" J Immunol 190(8): 4014-4026.PubMed

Follicular helper CD4 T cells (Tfh) are a special type of differentiated CD4 T cells that are specifically specialized to support B cells. In this study, we examined the fate of Tfh cells, including the distinguishing features of Tfh versus Th1 proliferation and survival. Using cell transfer approaches at early time points after acute viral infection, we show that early Tfh cells and Th1 cells largely determine cell fate as early as day three. However, Tfh cell proliferation was tightly regulated in a TCR-dependent manner. In the normal state, Tfh cells are still dependent on external cell fate signals from B cellsliveEnvironment. Unexpectedly, we found that Tfh cells share numerous phenotypic parallels with memory CD8 T-cell progenitors, including selective upregulation of IL-7Ralpha and a collection of associated genes. Consequently, early Tfh cells can develop and form dynamic memory cells. These data support the hypothesis that CD4 and CD8 T cells share important aspects of the memory progenitor cell gene expression program involving Bcl6 and that there is a strong relationship between Tfh cells and CD4 T cell memory development.

liveBlocked by CD28
Eberlein, J., et al. (2012). "Multiple layers of CD80/86-dependent costimulatory activity regulate primary, memory, and secondary T-cell immunity against choriomeningitis virus" J Virol 86(4): 1955-1970.PubMed

The lymphocytic choriomeningitis virus (LCMV) system is one of the most widely used models for the study of infectious diseases and the regulation of virus-specific T-cell immunity. However, LCMV-specific T-cell responses have long been considered relatively independent in terms of the activity of costimulatory and related regulatory pathways, and therefore distinct from the regulation of T-cell immunity directed against many other viral pathogens. Here, we reassessed the contribution of CD28-CD80/86 costimulation to the LCMV system using CD80/86-deficient mice, and our results show that disruption of CD28-CD80/86 signaling alters the size, phenotype, and/or functionality of the LCMV-specific CD8 T cell population ( +) and/or CD4(+) in all phases of the T cell response. Remarkably, the profound inhibition of secondary T-cell immunity in CD80/86-deficient mice immunized with LCMV was shown to be a complex synthesis of both the development of defective memory T-cells and the specific requirement for CD80, but not CD86, in the memory response. whereas a related experiment revealed a CD28-dependent but CD80/86-independent scenario of CD8(+) T-cell secondary immunity suggesting the existence of a CD28 ligand other than CD80/86. Furthermore, we provide evidence that regulatory T cells (T(REG)), whose homeostasis is altered in CD80/86(-/-) mice, convert to LCMV-specific CD8(+)- restricted in the presence of CD80. T cell responses contribute /86. Our observations may therefore provide a more coherent perspective on CD28-CD80/86 costimulation in T-cell antiviral immunity, which places the LCMV system in the common context of multiple defects induced by virus-specific T-cells in the absence of CD28-CD80 costimulation can be acquired. / 86.

in vitroStimulation/activation of T cells
Angkasekwinai, P., et al. (2010). "Regulation of IL-9 expression by IL-25 signaling" Nat Immunol 11(3): 250-256.PubMed

The physiological regulation of interleukin (IL)-9 expression, a cytokine traditionally thought to be associated with T(H)2, remains unclear. Here we show that IL-9-expressing T cells were generatedin vitroin the presence of transforming growth factor β and IL-4 express high levels of mRNA for IL-17 receptor B (IL-17RB), the receptor for IL-25. Treatment of these cells with IL-25 enhances IL-9 expressionin vitro. Furthermore, transgenic and retroviral overexpression of IL-17RB in T cells results in IL-25-induced IL-9 production that is independent of IL-4. In vivo, the IL-25-IL-17RB pathway regulates IL-9 expression in allergic airway inflammation. Therefore, IL-25 is a newly identified regulator of IL-9 expression.

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