scholarly journals Pathogenic CD4+ T cells recognizing an unstable peptide of insulin are directly recruited into islets bypassing local lymph nodes

2013 ◽  
Vol 210 (11) ◽  
pp. 2403-2414 ◽  
Author(s):  
James F. Mohan ◽  
Boris Calderon ◽  
Mark S. Anderson ◽  
Emil R. Unanue
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Diabetic Mouse ◽  
Cell Repertoire ◽  
Highly Pathogenic ◽  
Nonobese Diabetic ◽  
Predominant Component ◽  
Antigen Presenting

In the nonobese diabetic mouse, a predominant component of the autoreactive CD4+ T cell repertoire is directed against the B:9-23 segment of the insulin B chain. Previous studies established that the majority of insulin-reactive T cells specifically recognize a weak peptide-MHC binding register within the B:9-23 segment, that to the 12–20 register. These T cells are uniquely stimulated when the B:9-23 peptide, but not the insulin protein, is offered to antigen presenting cells (APCs). Here, we report on a T cell receptor (TCR) transgenic mouse (8F10) that offers important new insights into the biology of these unconventional T cells. Many of the 8F10 CD4+ T cells escaped negative selection and were highly pathogenic. The T cells were directly recruited into islets of Langerhans, where they established contact with resident intra-islet APCs. Immunogenic insulin had to be presented in order for the T cells to localize and cause disease. These T cells bypassed an initial priming stage in the pancreatic lymph node thought to precede islet T cell entry. 8F10 T cells induced the production of antiinsulin antibodies and islets contained immunoglobulin (IgG) deposited on β cells and along the vessel walls.

Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

2003 ◽  
Vol 90 (11) ◽  
pp. 813-822 ◽  
Author(s):  
Jagadeesh Bayry ◽  
Anastas Pashov ◽  
Srini Kaveri ◽  
Roseline d’Oiron ◽  
Natalie Stieltjes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Factor Viii ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Cell Receptor ◽  
Severe Hemophilia ◽  
Cell Repertoire ◽  
Human Factor Viii ◽  
Gene Usage

SummaryIn the present study, we have analyzed the T cell receptor (TCR) repertoires of CD4+ T cells isolated from peripheral blood of 10 inhibitor-positive patients with severe hemophilia A. The distribution of complementarity determining region (CDR3) lengths of the beta chain of the TCRs was analyzed by spectratyping prior to and following in vitrostimulation of the cells with human factor VIII (FVIII). The repertoires of CD4+ T cells of patients were perturbed when compared to those of healthy blood donors. The perturbations of T cell repertoires were heterogeneous among patients with respect to the number and the nature of V-beta (BV) families that exhibited expansion following incubation with FVIII. Some patients showed alterations in one or two BV families, others exhibited more perturbed repertoires affecting 5 to 8 of the 14 BV families tested. Alterations of BV2, BV5 and/or BV9 were consistently found after incubation of CD4+ T cells in the presence of FVIII in 80% of the patients. These findings indicate that the presence of FVIII inhibitors in patients with severe hemophilia A is associated with measurable perturbations of the CD4+ T cell repertoire that results from oligoclonal expansion of FVIII-specific cells and may be relevant for the design of strategies aimed at modulating the anti-FVIII immune responses by T cell-targeted therapy

scholarly journals T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection.

1992 ◽  
Vol 176 (2) ◽  
pp. 459-468 ◽  
Author(s):  
R Abe ◽  
Y Ishida ◽  
K Yui ◽  
M Katsumata ◽  
T M Chused
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antigen Presenting ◽  
Self Antigen ◽  
Selection Of

Shaping of the T cell repertoire by selection during intrathymic maturation involves T cell receptor (TCR) recognition of major histocompatibility complex/self-antigen complexes. In this communication, we studied the ability of minor lymphocyte stimulating (Mls) determinants to act as self-tolerogens in the selection of the T cell repertoire. We demonstrate that unprimed T cells from normal as well as TCR transgenic mice form Mls-specific conjugates with antigen-presenting cells, and that this TCR-ligand interaction leads to elevation of intercellular Ca2+ ([Ca2+]i). Peripheral T cells from TCR transgenic mice expressing receptors specific for self-Mls antigen show no reactivities to Mlsa. However, a proportion of immature thymocytes from these mice show specific binding and strong [Ca2+]i elevation in response to self-antigen-presenting cells, although these thymocytes do not proliferate. This self-reactivity of thymocytes is inhibited by antibodies specific for TCR, CD4, CD8, class II molecules, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. These results demonstrate for the first time that before thymic negative selection, immature T cells can specifically interact with cells bearing self-antigen, and suggest that the resulting TCR-dependent signal transduction events provide a basis for negative selection of self-reactive T cells.

scholarly journals Simplified Monitoring of CD4 T-Cell Receptor Repertoire Provides Effective Management Strategies in the Patients with Persistent or Recurrent Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1162-1162
Author(s):  
Rie Kuroda ◽  
Shintaro Mase ◽  
Hideaki Maeba ◽  
Raita Araki ◽  
Yasuhiro Ikawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immunosuppressive Agents ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Graft Versus Host ◽  
Hla Dr ◽  
Tcr Repertoire ◽  
Immunological Recovery

Abstract T-cell receptor (TCR) repertoire has been studied regarding graft-versus-host disease (GVHD), graft-versus-tumor effect, and immunological recovery in hematopoietic stem cell transplantation (HSCT) as well as autoimmune diseases. It is unclear yet whether a TCR restriction is a useful marker for a decision on courses of treatment for persistent or recurrent GVHD, such as increase or tapering of immunosuppressive agents. Ninety-four peripheral blood samples obtained from 42 HSCT recipients (39 surviving more than one year and 3 surviving more than 6 months) and 30 healthy volunteers were analyzed. The relative TCR Vb usage of CD4+ and CD8+ T-cells was investigated using a panel of monoclonal antibodies specific for 21 different Vb regions by flow cytometry. A valuable describing the degree of Vb-repertoire restriction was defined, namely cumulative deviation index (CDI) calculated as shown in figure 1; the higher number of CDI indicated the more restricted pattern of TCR repertoire usage. CDI of TCR repertoire in CD4 T-cells 6 months later after HSCT was much higher in the patients with persistent or recurrent GVHD treated with steroids, compared with the patients without persistent or recurrent GVHD (p<0.05 as shown in Figure 2A). On the other hand, any specific findings were not obtained from CDI in CD8 T-cells. Interestingly, much more restriction of TCR repertoire in CD4 T-cells was observed in the patients who could not stop steroids in the future, compared with the patients who could discontinue them in the near future (p<0.05 as shown in Figure 2B). Next when combined with representative T-cell activation marker such as HLA-DR, we have found that immunosuppressive therapy could be discontinued finally when TCR repertoire in CD4 T-cells not CD8 recovered and maintained normal ranges even if HLA-DR were highly expressed (>=30% on CD4). Instead, when CDI of TCR repertoire in CD4 maintained relatively high level even if HLA-DR were below 30% on CD4, complete discontinuation of immunosuppressive agents was quite difficult. Finally we studied the correlation between TCR repertoire and the frequency of regulatory T-cells (Tregs). Some patients clearly demonstrated that the frequency of Tregs increased over time in concert with recovering of CD4 T-cell repertoire. However we were not able to show this trend in all patients, probably due to the administration of calcineurin inhibitors, which negatively affect the reconstitution of Tregs compared with those of conventional T-cells. Although much more detailed analysis of T-cell repertoire could be done recently by utilizing high-throughput sequencing, our method based on flow cytometry has a cost advantage and are easy to monitor the patients for immunological recovery. In conclusion, monitoring of TCR repertoire restriction in CD4 T-cells but not CD8 provides useful information for managements of the patients with prolonged GVHD. Special attention should be paid to the patients with strong restriction of TCR repertoire in CD4 T-cells. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2713
Author(s):  
Sun-Hye Shin ◽  
Kyung-Ah Cho ◽  
Hee-Soo Yoon ◽  
So-Yeon Kim ◽  
Hee-Yeon Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Acyl Chain ◽  
Signal Strength ◽  
Cell Receptor ◽  
Ceramide Synthase ◽  
Asthmatic Patients

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

scholarly journals Functional Uncoupling of T-cell Receptor Engagement and Lck Activation in Anergic Human Thymic CD4+T Cells

2001 ◽  
Vol 276 (20) ◽  
pp. 17455-17460 ◽  
Author(s):  
Wakae Fujimaki ◽  
Makio Iwashima ◽  
Junji Yagi ◽  
Hua Zhang ◽  
Hisako Yagi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor

scholarly journals T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mai T. Tran ◽  
Pouya Faridi ◽  
Jia Jia Lim ◽  
Yi Tian Ting ◽  
Goodluck Onwukwe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Type I Diabetes ◽  
Binding Motif ◽  
Type I ◽  
Cell Repertoire ◽  
Islet Amyloid ◽  
Autoreactive T Cell ◽  
Β Chain

AbstractHLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.

scholarly journals CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

2002 ◽  
Vol 196 (4) ◽  
pp. 481-492 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Mark Lee ◽  
Erik Ranheim ◽  
Cheng Chi Chao ◽  
Maija Sanna ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Glutamic Acid Decarboxylase ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Acid Decarboxylase ◽  
Gad 65

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

T-CELL RECEPTOR INDEPENDENT ACTIVATION OF CD4+T-CELLS IN SEVERE ACUTE PANCREATITIS

Pancreas ◽  
2008 ◽  
Vol 37 (4) ◽  
pp. 468
Author(s):  
A. Dummer ◽  
M. Sendler ◽  
F.-U. Weiss ◽  
B. M. Bröker ◽  
M. M. Lerch ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Pancreatitis ◽  
T Cell ◽  
T Cell Receptor ◽  
Severe Acute Pancreatitis ◽  
Cd4 T Cells ◽  
Cell Receptor

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

Sign in / Sign up

Export Citation Format

Share Document