scholarly journals Cytokine priming of naïve CD8+ T lymphocytes modulates chromatin accessibility that partially overlaps with changes induced by antigen simulation

2020 ◽  
Author(s):  
Akouavi Julite Quenum ◽  
Maryse Cloutier ◽  
Madanraj Appiya Santharam ◽  
Marian Mayhue ◽  
Sheela Ramanathan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Molecular Mechanisms ◽  
Chromatin Accessibility ◽  
Antigenic Peptides ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Altered Peptide Ligands ◽  
Signaling Activation

AbstractBackgroundNaïve CD8+ T lymphocytes undergo antigen non-specific proliferation following exposure to certain synergistic combination of inflammatory (IL-6, IL-21) and homeostatic (IL-7, IL-15) cytokines. Such cytokine-stimulated naïve CD8+ T cells display increased T cell antigen receptor (TCR) sensitivity, allowing them to respond to limiting concentrations of cognate antigenic peptides and altered peptide ligands of lower affinity towards the TCR. The purpose of this study is to gain insight into the molecular mechanisms of such ‘cytokine priming’.MethodsNaïve CD8+ T lymphocytes expressing the PMEL-1 transgenic TCR were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. Cells stimulated by the cognate antigenic peptide mgp10025-33 were used as controls.ResultsCompared to naïve cells, cytokine-primed cells showed 212 opening and 484 closing peaks, whereas antigen-stimulated cells showed 12087 opening and 6982 closing peaks. However, a significant fraction of the opening (33%) and closing (63%) peaks of cytokine-primed cells overlapped with those of the antigenic stimulated cells. Chromatin accessibility peaks modulated in cytokine-primed cells were strongly represented in gene ontology pathways for T cell signaling, activation, regulation and effector functions. Many of the transcription factor binding motifs located close to the opening and closing peaks of cytokine-primed cells also occurred in antigen-stimulated cells.ConclusionsOur data suggest that by modulating the gene expression programs involved in TCR signaling, cytokine priming induces a poised state that lowers the TCR signaling threshold in naïve CD8+ T cells and increases their antigen responsiveness.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

scholarly journals Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway

2020 ◽  
Vol 295 (8) ◽  
pp. 2239-2247 ◽  
Author(s):  
Jeoung-Eun Park ◽  
David D. Brand ◽  
Edward F. Rosloniec ◽  
Ae-Kyung Yi ◽  
John M. Stuart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cell Signaling ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Cell Signaling Pathway

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1–sufficient and –deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ζ chain of T-cell receptor–associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1–induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog–sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.

scholarly journals DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation

2007 ◽  
Vol 27 (21) ◽  
pp. 7574-7581 ◽  
Author(s):  
Linda M. Stephenson ◽  
Bénédicte Sammut ◽  
Daniel B. Graham ◽  
Joaquim Chan-Wang ◽  
Karry L. Brim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Receptor ◽  
Suppressor Gene ◽  
Negative Regulator ◽  
Tcr Signaling ◽  
Mammalian Embryo ◽  
T Lymphocyte Proliferation ◽  
Discs Large

ABSTRACT Discs large homolog 1 (DLGH1), a founding member of the membrane-associated guanylate kinase family of proteins containing PostSynaptic Density-95/Discs large/Zona Occludens-1 domains, is an ortholog of the Drosophila tumor suppressor gene Discs large. In the mammalian embryo, DLGH1 is essential for normal urogenital morphogenesis and the development of skeletal and epithelial structures. Recent reports also indicate that DLGH1 may be a critical mediator of signals triggered by the antigen receptor complex in T lymphocytes by functioning as a scaffold coordinating the activities of T-cell receptor (TCR) signaling proteins at the immune synapse. However, it remains unclear if DLGH1 functions to enhance or attenuate signals emanating from the TCR. Here, we used Dlgh1 gene-targeted mice to determine the requirement for DLGH1 in T-cell development and activation. Strikingly, while all major subsets of T cells appear to undergo normal thymic development in the absence of DLGH1, peripheral lymph node Dlgh1 −/− T cells show a hyper-proliferative response to TCR-induced stimulation. These data indicate that, consistent with the known function of Discs large proteins as tumor suppressors and attenuators of cell division, in T lymphocytes, DLGH1 functions as a negative regulator of TCR-induced proliferative responses.

Cognate recognition of the endothelium induces HY-specific CD8+ T-lymphocyte transendothelial migration (diapedesis) in vivo

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3111-3116 ◽  
Author(s):  
Federica M. Marelli-Berg ◽  
Martha J. James ◽  
John Dangerfield ◽  
Julian Dyson ◽  
Maggie Millrain ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transendothelial Migration ◽  
Antigenic Peptides ◽  
In Vivo Models ◽  
Inflammatory Conditions ◽  
Peritoneal Mesothelium

Abstract The physiologic significance of MHC-peptide complex presentation by endothelial cells (ECs) to trafficking T lymphocytes remains unresolved. On the basis of our observation that cognate recognition of ECs enhanced transendothelial migration of antigen-specific T lymphocytes in vitro, we have proposed that by displaying antigenic peptides from the underlying tissue, ECs promote the recruitment of antigen-specific T cells. In this study, we have tested this hypothesis by comparing the trafficking of HY-specific T lymphocytes into antigenic and nonantigenic tissue using in vivo models of T-cell recruitment. Up-regulated expression of H2 molecules presenting endogenous antigen in the peritoneal mesothelium and vessels led to the local recruitment of HY-specific T cells in male, but not female, mice. Intravital microscopy experiments analyzing EC–HY-specific T-cell interactions in the cremasteric vascular bed revealed that cognate recognition of the endothelium results in enhanced diapedesis of T cells into the tissue, while not affecting rolling and adhesion. Our results are consistent with the hypothesis that, under inflammatory conditions, antigen presentation by the endothelium contributes to the development and specificity of T-cell–mediated inflammation by favoring the selective migration of antigen-specific T cells. (Blood. 2004;103:3111-3116)

210 Regulation of TIM-3 by phosphatidylserine

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A229-A229
Author(s):  
Courtney Smith ◽  
Alice Li ◽  
Nithya Krishnamurthy ◽  
Mark Lemmon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Cell Model ◽  
Cd8 T Cell ◽  
Receptor Expression ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Chimeric Receptors

BackgroundImmune checkpoint blockade has proven effective in targeting exhausted T-cells to reactivate the immune system against cancer. However, the majority of patients fail to respond to currently available therapies, which primarily target PD-1. Thus, a key challenge for checkpoint blockade therapy is to identify and understand new therapeutic targets. Another immune checkpoint receptor is TIM-3, which – like PD-1 – is expressed on exhausted T-cells in the tumor microenvironment.1, 2 TIM-3 belongs to a family of phosphatidylserine (PS) receptors, including TIM-1 and TIM-4, which have well-documented roles in the engulfment of apoptotic cells by phagocytes.3 However, the role of PS in regulating TIM-3 function is less clear. We therefore investigated how TIM-3 modulates T-cell signaling and how PS influences TIM-3 activity, with the ultimate goal of improving the translation of candidate TIM-3 therapies to the clinic.MethodsSurface plasmon resonance (SPR) was used to quantify the interaction between human TIM-3 and PS. A Jurkat T-cell model was used to investigate the role of TIM-3 in T-cell receptor (TCR) signaling and to determine the role of PS in regulating TIM-3 function.ResultsTIM-3 bound PS-containing membranes with low micromolar affinity in vitro. In the Jurkat cell model system, high – but not low – surface levels of TIM-3 promoted T-cell signaling, suggesting a threshold of receptor expression needed to modulate T-cell signaling, similar to what has recently been reported for PD-1.4 However, chimeric receptors that maintained the TIM-3 cytoplasmic tail but were unable to bind PS failed to enhance T-cell signaling like the full-length TIM-3 receptor. Cells expressing mutant TIM-3, which displayed reduced PS binding as quantified by SPR, also displayed reduced T-cell signaling compared to cells expressing wild-type TIM-3. Importantly, treatment of TIM-3-expressing cells with a functional TIM-3 antibody that blocks PS binding also reduced T-cell signaling compared with untreated TIM-3-expressing cells.ConclusionsOur results support a role for PS as a ligand capable of modulating TIM-3 activity. Using chimeric receptors, TIM-3 mutants, changes in receptor expression, and a functional TIM-3 antibody, we show that preventing the interaction between TIM-3 and PS blocks TIM-3 activity. These data suggest that blocking the PS-TIM-3 interaction is a key mechanism for functional antibodies targeting TIM-3. Ultimately, this work supports the development and use of clinical antibodies that block the interaction of TIM-3 with PS and provides new mechanistic insight into how TIM-3 modulates TCR signaling.AcknowledgementsThis work was supported by the PhRMA Foundation Pre-Doctoral Fellowship in Pharmacology/Toxicology.ReferencesFourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–2186.Zhou Q, Munger ME, Veenstra RG, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501–4510.Kobayashi N, Karisola P, Peña-Cruz V, et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27(6):927–940.Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355(6332):1428–1433.

scholarly journals Mutation of the CD28 Co-Stimulatory Domain Confers Enhanced CAR T Cell Function

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 248-248 ◽  
Author(s):  
Justin C. Boucher ◽  
Gongbo Li ◽  
Hiroshi Kotani ◽  
Maria Cabral ◽  
Dylan Morrissey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Research Funding ◽  
Chromatin Accessibility ◽  
Target Cells ◽  
T Cell Signaling ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

An obstacle with continued clinical development of CAR T cells is the limited understanding of their biology and mechanisms of anti-tumor immunity. We and others have shown that CARs with a CD28 co-stimulatory domain drive high levels of T cell activation that also lead to exhaustion and shortened persistence. The CD28 domain includes 3 intracellular subdomains (YMNM, PRRP, and PYAP) that regulate signaling pathways post TCR-stimulation, but it is unknown how they modulate activation and/or exhaustion of CAR T cells. A detailed understanding of the mechanism of CD28-dependent exhaustion in CAR T cells will allow the design of a CAR less prone to exhaustion and reduce relapse rates. This led us to hypothesize that by incorporating null mutations of CD28 subdomains (Fig 1A) we could optimize CAR T cell signaling and reduce exhaustion. In vitro, we found mutated CAR T cells with only a functional PYAP (mut06) subdomain secrete significantly less IFNγ, IL6, and TNFα after 24hr stimulation compared to non-mutated CD28 CAR T cells, but greater than the 1st generation m19z CAR. Also, cytotoxicity was enhanced compared to non-mutated CARs (Fig 1B). Using a pre-clinical immunocompetent mouse tumor model, we found the mut06 CAR T cell treated mice had a significant survival advantage compared to non-mutated CD28 CAR T cells (Fig 1C). To examine exhaustion, we ex vivo stimulated CAR T cells with target cells expressing CD19 and PDL1 and found mut06 CAR T cells had increased IFNγ (42%), TNFα (62%) and IL2 (73%) secretion compared to exhausted non-mutated CD28 CAR T cells. This suggests that mut06 CAR T cells are more resistant to exhaustion. To find a mechanistic explanation for this observation we examined CAR T cell signaling. After 24hr stimulation with CD19 target cells mut06 CAR T cells had a significant reduction in pAkt compared to m1928z CAR T cells, which is a critical signaling mediator in the NFAT and NR4A1 transcription factor pathways. Additionally, mut06 had decreased p-NFAT compared to m1928z when examined by western blot. To determine how optimized CAR signaling affected T cell exhaustion we looked at 22 genes that are upregulated when NFAT is constitutively active and overlap with genes identified as important for T cell exhaustion. We found that most of the exhaustion related genes were upregulated in m1928z CAR T cells while they were decreased in m19hBBz. The mut06 CAR T cell gene expression pattern was more similar to m19hBBz with exhaustion related genes downregulated compared to m1928z (Fig 1D). To examine differences in the accessibility of exhaustion related genes we performed ATAC-seq and found NFAT (Nfatc1) and NR4A2 (Nr4a2) had lower chromatin accessibility profiles in mut06 compared to m1928z (Fig 1E). We also found that exhaustion related genes Havcr2 (TIM3), Pdcd1 (PD1), and Lag3 (LAG3) all had greatly reduced chromatin accessibility in mut06 CAR T cells compared m1928z. Overall, these genomic studies support our findings that mut06 optimizes CAR T cell signaling by lowering transcription factors that regulate exhaustion. Figure 1 Disclosures Li: ImmuneBro Therapeutics: Other: sole shareholder . Davila:Atara: Research Funding; Celgene: Research Funding; GlaxoSmithKline: Consultancy; Novartis: Research Funding; Anixa: Consultancy; Bellicum: Consultancy; Adaptive: Consultancy; Precision Biosciences: Consultancy.

scholarly journals A Pivotal Role for Interleukin-27 in CD8+T Cell Functions and Generation of Cytotoxic T Lymphocytes

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Noriko Morishima ◽  
Izuru Mizoguchi ◽  
Masae Okumura ◽  
Yukino Chiba ◽  
Mingli Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Critical Issue ◽  
Cell Functions ◽  
Antitumor Immunotherapy

Cytotoxic T lymphocytes (CTLs) play a critical role in the control of various cancers and infections, and therefore the molecular mechanisms of CTL generation are a critical issue in designing antitumor immunotherapy and vaccines which augment the development of functional and long-lasting memory CTLs. Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, acts on naiveCD4+T cells and plays pivotal roles as a proinflammatory cytokine to promote the early initiation of type-1 helper differentiation and also as an antiinflammatory cytokine to limit the T cell hyperactivity and production of pro-inflammatory cytokines. Recent studies revealed that IL-27 plays an important role inCD8+T cells as well. Therefore, this article reviews current understanding of the role of IL-27 inCD8+T cell functions and generation of CTLs.

scholarly journals DOK1 and DOK2 regulate CD8+ T cell signaling and memory formation without affecting tumor cell killing

2021 ◽  
Author(s):  
Vladimir Laletin ◽  
Pierre-Louis Bernard ◽  
Montersino Camille ◽  
Yuji Yamanashi ◽  
Daniel Olive ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Progression ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Effector Memory ◽  
T Cell Signaling ◽  
Tcr Signaling

Targeting intracellular inhibiting proteins is a promising strategy to improve CD8+ T cell anti-tumor efficacy. DOK1 and DOK2 are CD8+ T cell inhibitory proteins that are targeted in this study in order to improve the activation and cytotoxic capacities of these cells. To evaluate the role of DOK-1 and DOK-2 depletion in physiology and effector function of T CD8+ lymphocyte and in cancer progression, a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) was established. Depletion of both Dok1 and Dok2 did not affect the development, proliferation, mortality, activation and cytotoxic function of naive CD8+ T cells. However, after an in vitro pre-stimulation Dok1/Dok2 DKO CD8+ T cells had higher percentage of effector memory T cells and showed an increase in levels of pAKT and pERK upon TCR stimulation. Despite this improved TCR signaling, pre-stimulated Dok1/Dok2 DKO CD8+ T cells did not show any increase in their activation or cytotoxicity capacities against melanoma cell line expressing hgp100 in vitro. Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8+ T cells. In conclusion, DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.

scholarly journals CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3–kinase– independent manner

2007 ◽  
Vol 204 (5) ◽  
pp. 1167-1179 ◽  
Author(s):  
François Asperti-Boursin ◽  
Eliana Real ◽  
Georges Bismuth ◽  
Alain Trautmann ◽  
Emmanuel Donnadieu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Motility ◽  
Molecular Mechanisms ◽  
Experimental System ◽  
Cell Polarization ◽  
Minor Role ◽  
Independent Manner ◽  
Phosphoinositide 3 Kinase

The molecular mechanisms responsible for the sustained basal motility of T cells within lymph nodes (LNs) remain elusive. To study T cell motility in a LN environment, we have developed a new experimental system based on slices of LNs that allows the assessment of T cell trafficking after adoptive transfer or direct addition of T cells to the slice. Using this experimental system, we show that T cell motility is highly sensitive to pertussis toxin and strongly depends on CCR7 and its ligands. Our results also demonstrate that, despite its established role in myeloid cell locomotion, phosphoinositide 3–kinase (PI3K) activity does not contribute to the exploratory behavior of the T lymphocytes within LN slices. Likewise, although PI3K activation is detectable in chemokine-treated T cells, PI3K plays only a minor role in T cell polarization and migration in vitro. Collectively, our results suggest that the common amplification system that, in other cells, facilitates large phosphatidylinositol 3,4,5-trisphosphate increases at the plasma membrane is absent in T cells. We conclude that T cell motility within LNs is not an intrinsic property of T lymphocytes but is driven in a PI3K-independent manner by the lymphoid chemokine-rich environment.

scholarly journals A Single L/D-Substitution at Q4 of the mInsA2-10 Epitope Prevents Type 1 Diabetes in Humanized NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengjun Zhang ◽  
Yuanqiang Wang ◽  
Xiangqian Li ◽  
Gang Meng ◽  
Xiaoling Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Altered Peptide Ligands

Autoreactive CD8+ T cells play an indispensable key role in the destruction of pancreatic islet β-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential β-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA2-10) is an immunodominant ligand for autoreactive CD8+ T cells in NOD.β2mnull.HHD mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses via triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA2-10, named mInsA2-10DQ4 and mInsA2-10DC6, respectively. We found that administration of mInsA2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.β2mnull.HHD mice. Mechanistically, treatment with mInsA2-10DQ4 not only notably eliminated mInsA2-10 autoreactive CD8+ T cell responses but also prevented the infiltration of CD4+ T and CD8+ T cells, as well as the inflammatory responses in the pancreas of NOD.β2mnull.HHD mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.

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