scholarly journals Gender-Related Differences in the Rates of Age Associated Thymic Atrophy

2001 ◽  
Vol 8 (2) ◽  
pp. 95-106 ◽  
Author(s):  
Richard Aspinall ◽  
Deborah Andrew
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Male Mice ◽  
Thymic Atrophy ◽  
Female Mice ◽  
Age Related ◽  
Significant Difference ◽  
Peripheral T Cells ◽  
Β Chain ◽  
Early Phases

Age associated thymic atrophy has been shown to be linked to problems with rearrangement of the β chain of the T cell receptor (TCR) in male mice during the early phases of the intrathymic T cell developmental pathway. In this study, thymic atrophy in female mice was found to occur at a different rate than in male mice. At 9 months of age there was a significantly greater number of cells in the thymus of female mice compared with male mice, with the major difference found in the CD4+CD8+populations. The thymii of female mice at 9 months of age contained double the number of these cells compared with male mice. Analysis of the CD4+CD8+cells at 9 months of age demonstrated increased numbers of cells expressing higher levels of CD3 in females compared with males indicating that in females more of these cells were producing successful αβTCR pairings. In F5 transgenic mice comparison of the CD4+CD8+population revealed no significant difference in their absolute numbers at 9 months of age. These results indicate that the gender differences at this time point were due to fewer permitted divisions prior to the expression of a selectable TCR α chain within the CD4+CD8+populations in male compared with female mice. This gender difference was not due to the action of testosterone and unlikely to be due to differences in the level of oestrogen. The potential mechanisms of this difference may be related to a regulatory feedback of peripheral T cells on the developing thymocyte populations. Such age related changes in the numbers of cells within distinct thymic subpopulations leads to the possibility that the potential repertoire in females is greater than in males later in life.

scholarly journals Characteristics of profiling the peripheral blood T-cell receptor β-chain repertoire in gastric cancer

2020 ◽  
Author(s):  
YANWEN LIU YANWEN LIU ◽  
Nan nan Guo Nan nan Guo ◽  
Yi ting Wu Yi ting Wu ◽  
Yu hua Shi Yu hua Shi
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Advanced Gastric Cancer ◽  
Cancer Patients ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Significant Difference ◽  
Tcr Repertoire ◽  
Β Chain

Abstract Background: Gastric cancer is the third cause of cancer-related deaths worldwide, and is initially detected and attacked by the immune system through tumor-reactive T cells. The aim of this study was to determine the basic characteristics of the peripheral blood T-cell receptor (TCR) repertoire in patients with gastric cancer. Methods: High throughput sequencing was used to identify hyper-variable rearrangements of complementarity determining region 3 (CDR3) of the TCR β chain to comprehensively profile the TCR repertoire in peripheral blood samples from 6 advanced gastric cancer patients and 3 early gastric cancer controls. Results: The study showed that the TCR repertoire differed substantially between advanced cancer patients and early controls in terms of CDR3 clonotype, diversity and V/J segment usage. Specifically, low diversity reflected a worse immune status and prognosis in advanced gastric cancer. However the diversity of TCR was not significant difference in wild or mutation patients. Conclusion: TCR repertoire analysis served as a useful indicator of disease development and prognosis in gastric cancer and may be utilized to be biomarker for immunotherapy.

scholarly journals Cytomegalovirus-Mediated T Cell Receptor Repertoire Perturbation Is Present in Early Life

2020 ◽  
Vol 11 ◽  
Author(s):  
Meriem Attaf ◽  
Julia Roider ◽  
Amna Malik ◽  
Cristina Rius Rafael ◽  
Garry Dolton ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Early Life ◽  
Cell Receptor ◽  
T Cell Response ◽  
Sub Saharan Africa ◽  
Direct Result ◽  
Age Related ◽  
Tcr Repertoire ◽  
Β Chain

Human cytomegalovirus (CMV) is a highly prevalent herpesvirus, particularly in sub-Saharan Africa, where it is endemic from infancy. The T cell response against CMV is important in keeping the virus in check, with CD8 T cells playing a major role in the control of CMV viraemia. Human leukocyte antigen (HLA) B*44:03-positive individuals raise a robust response against the NEGVKAAW (NW8) epitope, derived from the immediate-early-2 (IE-2) protein. We previously showed that the T cell receptor (TCR) repertoire raised against the NW8-HLA-B*44:03 complex was oligoclonal and characterised by superdominant clones, which were shared amongst unrelated individuals (i.e., “public”). Here, we address the question of how stable the CMV-specific TCR repertoire is over the course of infection, and whether substantial differences are evident in TCR repertoires in children, compared with adults. We present a longitudinal study of four HIV/CMV co-infected mother-child pairs, who in each case express HLA-B*44:03 and make responses to the NW8 epitope, and analyse their TCR repertoire over a period spanning more than 10 years. Using high-throughput sequencing, the paediatric CMV-specific repertoire was found to be highly diverse. In addition, paediatric repertoires were remarkably similar to adults, with public TCR responses being shared amongst children and adults alike. The CMV-specific repertoire in both adults and children displayed strong fluctuations in TCR clonality and repertoire architecture over time. Previously characterised superdominant clonotypes were readily identifiable in the children at high frequency, suggesting that the distortion of the CMV-specific repertoire is incurred as a direct result of CMV infection rather than a product of age-related “memory inflation.” Early distortion of the TCR repertoire was particularly apparent in the case of the TCR-β chain, where oligoclonality was low in children and positively correlated with age, a feature we did not observe for TCR-α. This discrepancy between TCR-α and -β chain repertoire may reflect differential contribution to NW8 recognition. Altogether, the results of the present study provide insight into the formation of the TCR repertoire in early life and pave the way to better understanding of CD8 T cell responses to CMV at the molecular level.

Immunosenescence: potential causes and strategies for reversal

2000 ◽  
Vol 28 (2) ◽  
pp. 250-254 ◽  
Author(s):  
R. Aspinall ◽  
D. Andrew
Keyword(s):  
T Cell ◽  
Immune Dysfunction ◽  
Careful Analysis ◽  
Experimental Therapy ◽  
Thymic Involution ◽  
Interleukin 7 ◽  
Cell Pool ◽  
Age Related ◽  
Peripheral T Cells ◽  
Laboratory Investigations

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

scholarly journals Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice

2016 ◽  
Vol 113 (5) ◽  
pp. 1333-1338 ◽  
Author(s):  
Kylie M. Quinn ◽  
Sophie G. Zaloumis ◽  
Tania Cukalac ◽  
Wan-Ting Kan ◽  
Xavier Y. X. Sng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Clonal Diversity ◽  
Cell Receptor ◽  
Advanced Age ◽  
Age Related ◽  
Self Recognition ◽  
Underlying Mechanisms

In advanced age, decreased CD8+ cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8+ T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8+ T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8+ T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8+ T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8+ T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging.

Restricted usage of T-cell receptor α-chain variable region (TCRAV) and T-cell receptor β-chain variable region (TCRBV) repertoires after human allogeneic haematopoietic transplantation

2000 ◽  
Vol 109 (4) ◽  
pp. 759-769 ◽  
Author(s):  
Takaji Matsutani ◽  
Takeshi Yoshioka ◽  
Yuji Tsuruta ◽  
Shoji Iwagami ◽  
Tomoko Toyosaki-Maeda ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Variable Region ◽  
Cell Receptor ◽  
Α Chain ◽  
Β Chain

Specificity and T cell receptor β chain usage of a human collagen type II-reactive T cell clone derived from a healthy individual

1992 ◽  
Vol 22 (1) ◽  
pp. 51-56 ◽  
Author(s):  
Tan Yan ◽  
Harald Burkhardt ◽  
Thomas Ritter ◽  
Barbara Bröker ◽  
Karl Heinz Mann ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Collagen Type ◽  
Cell Clone ◽  
Cell Receptor ◽  
Type Ii ◽  
Collagen Type Ii ◽  
T Cell Clone ◽  
Human Collagen ◽  
Β Chain

T-cell receptor variable region of the β-chain gene use in peripheral blood and multiple synovial membranes during rheumatoid arthritis

1995 ◽  
Vol 42 (4) ◽  
pp. 331-339 ◽  
Author(s):  
Antoine Alam ◽  
Jacqueline Lulé ◽  
Héléne Coppin ◽  
Nathalie Lambert ◽  
Bernard Maziéres ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Variable Region ◽  
Cell Receptor ◽  
Chain Gene ◽  
Synovial Membranes ◽  
Β Chain

T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4087-4087
Author(s):  
Patricia McCoon ◽  
Young S Lee ◽  
Robin Kate Kelley ◽  
Violeta Beleva Guthrie ◽  
Song Wu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Single Agent ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Combination Regimen ◽  
Cell Counts ◽  
Significant Difference ◽  
Dose Dependent ◽  
Cell Clonal Expansion

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

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