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

scholarly journals Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2112-2121 ◽  
Author(s):  
Paria Mirmonsef ◽  
Gladys Tan ◽  
Gang Zhou ◽  
Tricia Morino ◽  
Kimberly Noonan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution ◽  
Effector T Cells ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Tumor Bearing ◽  
Specific Effector

Immune reconstitution of autologous hematopoietic stem-cell transplant recipients with the progeny of mature T cells in the graft leads to profound changes in the emerging functional T-cell repertoire. In the steady state, the host is frequently tolerant to tumor antigens, reflecting dominant suppression of naive and effector T cells by regulatory T cells (Tregs). We examined the relative frequency and function of these 3 components within the tumor-specific T-cell compartment during immune reconstitution. Grafts from tumor-bearing donors exerted a significant antitumor effect in irradiated, syngeneic tumor-bearing recipients. This was associated with dramatic clonal expansion and interferon-γ (IFNγ) production by previously tolerant tumor-specific T cells. While donor-derived Tregs expanded in recipients, they did not inhibit the antigen-driven expansion of effector T cells in the early posttransplantation period. Indeed, the repopulation of tumor-specific effector T cells significantly exceeded that of Tregs, the expansion of which was limited by IL-2 availability. Although the intrinsic suppressive capacity of Tregs remained intact, their diminished frequency was insufficient to suppress effector cell function. These findings provide an explanation for the reversal of tolerance leading to tumor rejection in transplant recipients and likely contribute to the efficacy of adoptive T-cell therapies in lymphopenic hosts.

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.

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 CTLA-4–B7 Interaction Is Sufficient to Costimulate T Cell Clonal Expansion

1997 ◽  
Vol 185 (7) ◽  
pp. 1327-1336 ◽  
Author(s):  
Yan Wu ◽  
Yong Guo ◽  
Andy Huang ◽  
Pan Zheng ◽  
Yang Liu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Critical Role ◽  
Clonal Expansion ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
Cell Clonal Expansion

T cell costimulation, particularly by the B7 family members B7-1 and B7-2, plays a critical role in regulating T cell–mediated immunity. Two molecules on T cells, CD28 and CTLA-4, are known to bind to B7. It has been suggested that CD28–B7 interaction promotes T cell response, whereas B7–CTLA-4 interaction downregulates T cell clonal expansion. However, the proposed responses of individual receptors to B7 have not been verified directly. Here, we report that B7-1 promotes clonal expansion of CD28-deficient T cells, and that the CD28-independent costimulatory activity is mediated by CTLA-4, as it is completely blocked by intact and Fab of anti–CTLA-4 mAb. In addition, a mutant B7-1 molecule, B7W88 >A, which has lost binding to CD28 but retained significant CTLA-4 binding activity, promotes T cell clonal expansion. Furthermore, while presence of CD28 enhances T cell response to B7-1, such response is also completely blocked by anti–CTLA-4 mAb. Taken together, our results demonstrate that B7–CTLA-4 interaction promotes T cell clonal expansion, and that optimal T cell response to B7 is achieved when both CD28 and CTLA-4 interact with B7. These results establish an important function of CTLA-4 in promoting T cell activation, and suggest an alternative interpretation of the function of CTLA-4 in T cell activation.

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.

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