scholarly journals Nasal Delivery of Antigen with the B Subunit of Escherichia coli Heat-Labile Enterotoxin Augments Antigen-Specific T-Cell Clonal Expansion and Differentiation

2004 ◽  
Vol 72 (7) ◽  
pp. 4072-4080 ◽  
Author(s):  
Maria Apostolaki ◽  
Neil A. Williams
Keyword(s):  
Escherichia Coli ◽  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Clonal Expansion ◽  
Transfer Model ◽  
B Subunit ◽  
Heat Labile ◽  
Dividing Cells ◽  
Cell Clonal Expansion

ABSTRACT Escherichia coli heat-labile enterotoxin has unique immunogenic and adjuvant properties when administered mucosally to mice. These properties have revealed the potential for its use in the development of mucosal vaccines, an area of increasing interest. However, the inherent toxicity mediated by the A subunit precludes its widespread use. This problem has led to attempts to dissociate toxicity from adjuvant function by use of the B subunit. The ability of the B subunit of E. coli heat-labile enterotoxin (EtxB) to enhance responses against antigens coadministered intranasally is demonstrated here with the use of the DO11.10 adoptive-transfer model, in which ovalbumin (OVA)-specific adoptively transferred T cells can be monitored directly by flow cytometry. Intranasal delivery of OVA with EtxB resulted in increased T-cell proliferative and systemic antibody responses against antigens. The increased Th2 cytokine production detected following in vitro restimulation of splenocyte and cervical lymph node (CLN) cells from the immunized mice correlated with increased OVA-specific immunoglobulin G1 antibody production. Flow cytometric analysis of T cells from mice early after immunization directly revealed the ability of EtxB to support antigen-specific clonal expansion and differentiation. Furthermore, while responses were first detected in the CLNs, they rapidly progressed to the spleen, where they were further sustained. Examination of CD69 expression on dividing cells supported the notion that activation induced by the presence of antigens is not sufficient to drive T-cell differentiation. Furthermore, a lack of CD25 expression on dividing cells suggested that EtxB-mediated T-cell clonal expansion may occur without a sustained requirement for interleukin 2.

EVIDENCE OF INTRAGRAFT T CELL CLONAL EXPANSION IN TOLERANT TRANSPLANT RECIPIENTS: IMPLICATIONS TO STUDY THE ORIGIN OF REGULATORY T CELLS.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S145
Author(s):  
Yuan Zhai ◽  
Jiye Li ◽  
Hirohisa Kato ◽  
Markus Hammer ◽  
Hans-Dieter Volk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Clonal Expansion ◽  
Transplant Recipients ◽  
Cell Clonal Expansion

The correlation between tumor microenvironment and the clonality of the T-cell repertoire in lung cancer and colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14524-e14524
Author(s):  
Hua Cao ◽  
Jingxian Duan ◽  
Shunda Jiang ◽  
Tianhao Mu ◽  
Ruilian Xu
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Clonal Expansion ◽  
T Helper ◽  
T Cell Clonality ◽  
Cell Clonality ◽  
Cell Clonal Expansion

e14524 Background: The tumor microenvironment has been shown to affect the responsiveness of immunotherapy. Effective anti-tumor immune response requires the activation and expansion of specific antigen-reactive T cell clones. It was reported that increased T cell clonality was associated with improved response to immunotherapy. However, what type of tumor microenvironment facilitates T cell clonal expansion remained controversial. The study aims to investigate the correlation between tumor microenvironment and the clonality of the T cell repertoire in lung cancer and colorectal cancer. Methods: 4 lung cancer patients and 4 colorectal cancer patients were enrolled in this study. Tumor tissues and peripheral blood samples were collected for RNA sequencing and T cell receptor CDR3 sequencing. The infiltration levels of 28 immune cells were estimated based on the mRNA expression of the genetic markers. The T cell clonality was defined as 1-Peilou’s evenness. Data were presented as mean± S.E.M. Results: The mean T cell clone counts in the blood samples of the 8 patients were 25676±4782 (ranging from 10259 to 45016), and the mean clonality of the TCR repertoires was 0.20±0.02 (ranging from 0.11 to 0.27). The clonality of T cells in colorectal cancer patients was similar to that of the lung cancer patients (0.22±0.02 versus 0.18±0.03, p = 0.31), showing comparable potentials of antigenic responses. The tumor infiltration of regulatory T cells, type 17 T helper cells, CD56bright natural killer cells, and natural killer cells varied greatly among patients, the coefficient of variation of those cells were 54.61%, 54.61%, 54.43%, and 55.62% respectively. In contrast, the coefficient of variation of monocytes was 23.34%, displaying a relatively even distribution among patients. The Pearson’s correlation coefficient was calculated to show the correlation between T cell clonality and the infiltration level of all 28 types of immune cells. Notably, only the infiltration of type 17 T helper cells significantly associated with T cell clonality, the positive correlation gave an R square value of 0.68 (r = 0.82, 95% confidence interval of 0.04-0.98, p = 0.04). The infiltration levels of CD4+ T cells, CD8+ T cells, regulatory T cells, type 1 and type 2 T cells, and gamma delta T cells were not affected by T cell clonal expansion. The expression of B cells, dendritic cells, macrophages, natural killer cells, and monocytes did not correlate with T cell clonal expansion. However, the abundance of neutrophils appears to positively correlate with T cell clonality (p = 0.09). Conclusions: The clonal expansion was significantly associated with the infiltration of type 17 T helper cells but not other subtypes of T cells, showing that the type 17 T helper cells are crucial to the antigenic responses in lung cancer and colorectal cancer. A neutrophil enriched tumor microenvironment may facilitate T cell clonal expansion.

Positive Impact of T-Cell Clonal Expansion On Overall Survival in Patients with High-Risk Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1572-1572 ◽  
Author(s):  
Amber Schmidt ◽  
Rami S. Komrokji ◽  
Jeffrey S. Painter ◽  
Dana E Rollison ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Lower Risk ◽  
Median Overall Survival ◽  
Clonal Expansion ◽  
T Cell Expansion ◽  
Cell Clonal Expansion

Abstract Abstract 1572 Poster Board I-598 Background Suppression of clonal T-cells has been linked to immunosuppressive therapy response in patients with lower-risk MDS and with other forms of autoimmune bone marrow failure suggesting that T-cell clonal expansion is pathogenic to bone marrow hematopoiesis. It is possible, however, that clonal T-cells expanding in response to leukemia-associated antigens (LAA) may ultimately suppress tumor progression through immunosurveillance. Our group previously identified clonal T-cell expansion in 50% of MDS patients (n=52) compared to 5% in age matched control (n=20) (results published by Epling-Burnette et al, Leukemia 21:659, 2007). There was no statistically significant association between clonal T cell expansion and WHO subtype, IPSS, karyotype, transfusion dependency, age or gender in a cross-sectional analysis. Identification of the prognostic importance of clonal T-cell expansion is an important decision point concerning immunosuppressive therapies. We report here on overall survival for both lower and higher-risk MDS patients based on clonal T-cell expansion status. Materials and Methods The original study enrolled 52 patients diagnosed with MDS and 20 healthy volunteers. Peripheral mononuclear cells were isolated and clonal T cells were identified through analysis of the complementarity determining region (CDR)-3 of the T-cell receptor (TCR) using multiplex TCR-Vβ(CDR3) PCR on genomic DNA and by flow-cytometric analysis of Vβ expanded families. In this study, we retrospectively reviewed records of the 52 patients identified previously after obtaining IRB approval. We compared outcome of patients with evidence of clonal T-cell expansion in the peripheral blood to patients without clonal T-cell expansion. Data collected included demographic characteristics, WHO subtype, cytopenias at diagnosis, karyotype, and IPSS, subsequent therapies, disease progression, and survival. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). Kaplan–Meier curves were used for estimates of median overall survival. Results Long-term follow up data were available on 48 of the original 52 MDS patients and 50% had evidence of clonal T-cell expansion (n=24). RCMD was the commonest WHO subtype among both groups (n=24, 50%) and more patients were lower-risk based on IPSS (n=32, 67%). No difference in median overall survival (OS) was observed among the two groups based on the status of clonal T-cell expansion (55.8 mo with clonal T-cell expansion and 58.3 mo without clonal T-cell expansion, P-value 0.76. Patients were then stratified by IPSS into low/int-1 (lower risk) and int-2/high (higher risk) groups for subset analysis. In patients with a low/int-1 IPSS risk classification, the trend in median OS (median OS 79 mo in the positive group n=14; and 76 mo in the negative cohort n=18) was similar in both groups and consistent with previously published data from the International MDS risk analysis workshop (IMRAW/IPSS) for patients with low/int-1 IPSS risk classification. Interestingly, patients with clonal T-cell expansion in the int-2/high (higher risk) IPSS MDS group (n=10) had a median OS of 30 mo compared to 12 month in the same IPSS risk group with no clonal T-cell expansion (n=6). Therefore, the presence of clonal T-cells in higher risk MDS patients was associated with an improved outcome compared to reported median OS in higher risk IPPS MDS patients in the IMRAW database. Out of the 48 patients 14 received azacitidine; only two of the 6 patients with clonal T cell expansion (33%) had a response to azacitidine compared to 5 out of 8 patients (63%) without clonal T cell expansion. Conclusions The exact etiology of the clonal T-cell expansion is not known but may be autoimmune, homeostatic or antigen-driven. Improved survival in higher-risk patients with clonal T-cell expansion suggests a distinct pathophysiological mechanism. T-cell response may be generated to LAA providing immuneosurveillance that may be an important mechanism to slow disease progression. Furthermore, certain immunological signatures may be used as predictive tools for response to treatment. This study suggests that clonal T-cell expansion may be an important molecular determinant associate of improved survival outcome and a prospective larger cohort is warranted to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Antigen presentation by mouse CD4+ T cells involving acquired MHC class II:peptide complexes: another mechanism to limit clonal expansion?

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2704-2710 ◽  
Author(s):  
Julia Y. S. Tsang ◽  
Jian Guo Chai ◽  
Robert Lechler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Clonal Expansion ◽  
Class Ii ◽  
Hybridoma Cells ◽  
Mhc Class Ii Molecules

Antigen presentation by activated human and rat CD4+ T cells has long been known to induce hyporesponsiveness due to a combination of anergy and apoptosis. It has been assumed that no such phenomenon occurs in mice due to the inability of mouse T cells to synthesize major histocompatibility complex (MHC) class II molecules. There have been several recent descriptions of the transfer of molecules, including MHC molecules, from antigen-presenting cells (APCs) to T cells. Here, we describe the acquisition of MHC class II molecules by T-cell receptor (TCR)–transgenic T cells and T-hybridoma cells following culture with APCs. Acquisition was markedly enhanced by T-cell activation either due to cognate recognition of antigen or anti-CD3 activation. When activation was induced by antigen recognition, preferential acquisition of complexes of class II molecules displaying cognate peptide was observed; in contrast, following activation by anti-CD3 the acquisition of class II molecules was MHC unrestricted. T cells that had acquired MHC class II:peptide complexes were able to act as APCs and induced proliferation and interleukin-2 secretion by resting T cells. However, when activated T cells that had acquired MHC class II:peptide complexes engaged in T:T interactions, this led to an increase in apoptosis and the induction of hyporesponsiveness. These results raise the possibility that the acquisition of MHC class II:peptide complexes by T cells during an immune response may serve to limit clonal expansion, including that induced by alloantigen following tissue or stem cell transplantation.

scholarly journals A Natural Immunological Adjuvant Enhances T Cell Clonal Expansion through a CD28-dependent, Interleukin (IL)-2–independent Mechanism

1998 ◽  
Vol 187 (2) ◽  
pp. 225-236 ◽  
Author(s):  
Alexander Khoruts ◽  
Anna Mondino ◽  
Kathryn A. Pape ◽  
Steven L. Reiner ◽  
Marc K. Jenkins
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Subcutaneous Administration ◽  
Clonal Expansion ◽  
T Cell Proliferation ◽  
Soluble Antigen ◽  
Wild Type ◽  
Cell Clonal Expansion

The adoptive transfer of naive CD4+ T cell receptor (TCR) transgenic T cells was used to investigate the mechanisms by which the adjuvant lipopolysaccharide (LPS) enhance T cell clonal expansion in vivo. Subcutaneous administration of soluble antigen (Ag) resulted in rapid and transient accumulation of the Ag-specific T cells in the draining lymph nodes (LNs), which was preceded by the production of interleukin (IL)-2. CD28-deficient, Ag-specific T cells produced only small amounts of IL-2 in response to soluble Ag and did not accumulate in the LN to the same extent as wild-type T cells. Injection of Ag and LPS, a natural immunological adjuvant, enhanced IL-2 production and LN accumulation of wild-type, Ag-specific T cells but had no significant effect on CD28-deficient, Ag-specific T cells. Therefore, CD28 is critical for Ag-driven IL-2 production and T cell proliferation in vivo, and is essential for the LPS-mediated enhancement of these events. However, enhancement of IL-2 production could not explain the LPS-dependent increase of T cell accumulation because IL-2–deficient, Ag-specific T cells accumulated to a greater extent in the LN than wild-type T cells in response to Ag plus LPS. These results indicate that adjuvants improve T cell proliferation in vivo via a CD28-dependent signal that can operate in the absence of IL-2.

scholarly journals Escherichia coli Enterotoxin B Subunit Triggers Apoptosis of CD8+ T Cells by Activating Transcription Factor c-Myc

2001 ◽  
Vol 69 (8) ◽  
pp. 4923-4930 ◽  
Author(s):  
Marco Soriani ◽  
Neil A. Williams ◽  
Timothy R. Hirst
Keyword(s):  
Escherichia Coli ◽  
T Cells ◽  
Transcription Factor ◽  
Receptor Binding ◽  
Protein Levels ◽  
B Subunit ◽  
Heat Labile ◽  
Activating Transcription Factor ◽  
Induced Apoptosis ◽  
Factor C

ABSTRACT Heat-labile enterotoxin from enterotoxinogenic Escherichia coli is not only an important cause of diarrhea in humans and domestic animals but also possesses potent immunomodulatory properties. Recently, the nontoxic, receptor-binding B subunit of heat-labile enterotoxin (EtxB) was found to induce the selective death of CD8+ T cells, suggesting that EtxB may trigger activation of proapoptotic signaling pathways. Here we show that EtxB treatment of CD8+ T cells but not of CD4+ T cells triggers the specific up-regulation of the transcription factorc-myc, implicated in the control of cell proliferation, differentiation, and death. A concomitant elevation in Myc protein levels was also evident, with peak expression occurring 4 h posttreatment. Preincubation with c-myc antisense oligodeoxynucleotides demonstrated that Myc expression was necessary for EtxB-mediated apoptosis. Myc activation was also associated with an increase of IκBα turnover, suggesting that elevated Myc expression may be dependent on NF-κB. When CD8+ T cells were pretreated with inhibitors of IκBα turnover and NF-κB translocation, this resulted in a marked reduction in both EtxB-induced apoptosis and Myc expression. Further, a non-receptor-binding mutant of EtxB, EtxB(G33D), was shown to lack the capacity to activate Myc transcription. These findings provide further evidence that EtxB is a signaling molecule that triggers activation of transcription factors involved in cell survival.

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