scholarly journals Skin T cells maintain their diversity and functionality in the elderly

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hanako Koguchi-Yoshioka ◽  
Elena Hoffer ◽  
Stanley Cheuk ◽  
Yutaka Matsumura ◽  
Sa Vo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
The Elderly ◽  
Elderly Individuals ◽  
Cell Diversity ◽  
Circulating T Cells ◽  
Effects Of Aging ◽  
And Function ◽  
Resident Memory T Cells

AbstractRecent studies have highlighted that human resident memory T cells (TRM) are functionally distinct from circulating T cells. Thus, it can be postulated that skin T cells age differently from blood-circulating T cells. We assessed T-cell density, diversity, and function in individuals of various ages to study the immunologic effects of aging on human skin from two different countries. No decline in the density of T cells was noted with advancing age, and the frequency of epidermal CD49a+ CD8 TRM was increased in elderly individuals regardless of ethnicity. T-cell diversity and antipathogen responses were maintained in the skin of elderly individuals but declined in the blood. Our findings demonstrate that in elderly individuals, skin T cells maintain their density, diversity, and protective cytokine production despite the reduced T-cell diversity and function in blood. Skin resident T cells may represent a long-lived, highly protective reservoir of immunity in elderly people.

scholarly journals Mapping the lineage relationship between CXCR5+ and CXCR5- CD4+ T cells in HIV infected human lymph nodes

2019 ◽  
Author(s):  
Daniel Del Alcazar ◽  
Yifeng Wang ◽  
Chenfeng He ◽  
Ben S. Wendel ◽  
Perla M. Del Río-Estrada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
B Cell ◽  
List Type ◽  
Follicular Helper ◽  
Cell Diversity ◽  
Circulating T Cells ◽  
And Function ◽  
Cxcr5 Expression

SummaryCXCR5 is a key surface marker expressed on follicular helper T (TFH) cells. We report here B cell help functionality in a population of CD4+ T cells isolated from primary human lymph nodes (LN) that lacked CXCR5 expression. This CXCR5- subset is distinguished from other CXCR5- CD4+ T cells by high PD-1 expression. Accumulation of CXCR5-PD-1+ T cells correlated with peripheral CD4+ T cell depletion and an increase in T-bet+ B cells in the LN, highlighting these atypical CD4+ T cells as a key component of lymphoid dysregulation during chronic HIV infection. By interrogating the phenotypic heterogeneity, functional capacity, TCR repertoire, transcriptional profile, and epigenetic state of CXCR5-PD-1+ T cells, we showed that CXCR5-PD-1+ T cells are related to CXCR5+PD-1+ T cells and provided evidence for the down regulation of CXCR5 following cell division as one mechanism for the absence of CXCR5 expression. Notably, CXCR5-PD-1+ T cells exhibited a migratory transcriptional program and contributed to circulating CXCR5-PD-1+ T cells with B cell help functionality in the peripheral blood. Thus, these data link LN pathology to circulating T cells and expand the current understanding on T cell diversity in the regulation of B cell responses during chronic inflammation.High dimensional profiling of activated CD4+ T cells in HIV infected lymph nodes revealed an accumulation of a CXCR5 negative subset.CXCR5-PD-1+CD4+ T cells exhibited TFH-like protein expression and function.CXCR5-PD-1+CD4+ T cells are related to TFH cells by clonal lineage and epigenetic similarity.CXCR5-PD-1+CD4+ T cells upregulate a migratory gene program and contribute to circulating T cells with B cell help functionality

scholarly journals 173 Expression of a membrane-tethered IL-15/IL-15 receptor fusion protein enhances the persistence of MSLN-targeted TRuC-T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A185-A185
Author(s):  
Michelle Fleury ◽  
Derrick McCarthy ◽  
Holly Horton ◽  
Courtney Anderson ◽  
Amy Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Great Promise ◽  
And Function

BackgroundAdoptive cell therapies have shown great promise in hematological malignancies but have yielded little progress in the context of solid tumors. We have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes the full complement of TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin (MSLN)-targeting TRuC-T cells (TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the depth of response, we evaluated strategies that can promote intra-tumoral T cell persistence and function. Among the common ??-chain cytokines, IL-15 uniquely supports the differentiation and maintenance of memory T cell subsets by limiting terminal differentiation and conferring resistance to IL-2 mediated activation-induced cell death (AICD). In the studies described here, we evaluated the potential of IL-15 as an enhancement to TRuC-T cell phenotype, persistence and function against MSLN+ targets.MethodsPrimary human T cells were activated and transduced with a lentiviral vector encoding an anti-MSLN binder fused to CD3ε alone or co-expressed with a membrane-tethered IL-15rα/IL-15 fusion protein (IL-15fu). Transduced T cells were expanded for 9 days and characterized for expression of the TRuC, IL-15rα and memory phenotype before subjecting them to in vitro functional assays to evaluate cytotoxicity, cytokine production, and persistence. In vivo efficacy was evaluated in MHC class I/II deficient NSG mice bearing human mesothelioma xenografts.ResultsIn vitro, co-expression of the IL-15fu led to similar cytotoxicity and cytokine production as TC-210, but notably enhanced T-cell expansion and persistence upon repeated stimulation with MSLN+ cell lines. Furthermore, the IL-15fu-enhanced TRuC-T cells sustained a significantly higher TCF-1+ population and retained a stem-like phenotype following activation. Moreover, the IL-15fu-enhanced TRuCs demonstrated robust in vivo expansion and intra-tumoral accumulation as measured by ex vivo analysis of TRuC+ cells in the tumor and blood, with a preferential expansion of CD8+ T cells. Finally, IL-15fu-enhanced TRuC-T cells could be observed in the blood long after the tumors were cleared.ConclusionsThese pre-clinical studies suggest that the IL-15fu can synergize with TC-210 to increase the potency and durability of response in patients with MSLN+ tumors.Ethics ApprovalAll animal studies were approved by the respective Institutional Animal Care and Use Committees.

scholarly journals Abnormal phenotypic distribution of regulatory and effector T cells in octogenarian and nonagenarian women

2015 ◽  
Vol 61 (4) ◽  
pp. 329-335
Author(s):  
Wilson de Melo Cruvinel ◽  
Danilo Mesquita Júnior ◽  
Júlio Antônio Pereira Araújo ◽  
Karina Carvalho Samazi ◽  
Esper Georges Kállas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Elderly Women ◽  
The Elderly ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Healthy Elderly ◽  
T Cell Phenotypes ◽  
Effects Of Aging

SummaryIntroduction:aging is associated with several immunologic changes. Regulatory (Treg) and effector T cells are involved in the pathogenesis of infectious, neoplastic, and autoimmune diseases. Little is known about the effects of aging on the frequency and function of these T cell subpopulations.Methods:peripheral blood mononuclear cells (PBMC) were obtained from 26 young (under 44 years old) and 18 elderly (above 80 years old) healthy women. T cell subpopulations were analyzed by flow cytometry.Results:elderly individuals had lower frequency of several activated effector T cell phenotypes as compared with young individuals: CD3+CD4+CD25+ (3.82±1.93 versus 9.53±4.49; p<0.0001); CD3+CD4+CD25+CD127+(2.39±1.19 versus 7.26±3.84; p<0.0001); CD3+CD4+CD25+ (0.41±0.22 versus 1.86±0.85, p<0.0001); and CD3+CD4+CD25highCD127+(0.06±0.038 versus 0.94±0.64, p<0.0001). Treg (CD3+CD4+CD25+CD127øFoxp3+) presented lower frequency in elderly individuals as compared to young adults (0.34±0.18 versus 0.76±0.48; p=0.0004) and its frequency was inversely correlated with age in the whole group (r=-0.439; p=0.013). The elderly group showed higher frequency of two undefined CD25øFoxp3+ phenotypes: CD3+CD4+CD25øFoxp3+(15.05±7.34 versus 1.65±1.71; p<0.0001) and CD3+CD4+CD25øCD127øFoxp3+(13.0±5.52 versus 3.51±2.87; p<0.0001).Conclusions:the altered proportion of different T cell subsets herein documented in healthy elderly women may be relevant to the understanding of the immunologic behavior and disease susceptibility patterns observed in geriatric patients.

scholarly journals Metabolic and functional impairment of CD8+ T cells from the lungs of influenza-infected obese mice

2020 ◽  
Author(s):  
William D. Green ◽  
Abrar E. Al-Shaer ◽  
Qing Shi ◽  
Nancie J MacIver ◽  
Melinda A. Beck ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Post Infection ◽  
Cytokine Production ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Obese Mice ◽  
Diet Induced Obesity ◽  
And Function

ABSTRACTBackgroundObesity increases influenza disease risk in millions of adults worldwide. In this study, we investigated the effect of diet-induced obesity on pulmonary CD8+ T cell metabolism and function as a mechanism of impairment.MethodsMale C57BL/6J mice were fed either control (10% kcal/g) or high-fat (60% kcal/g) diet. Sub-lethal A/PR/8/34 influenza virus infection generated a robust pulmonary immune response. T cell metabolism and function were assessed at day 10 and day 24 post infection.ResultsAt day 10 post infection, CD8+ T cells from obese mice had impaired oxidative and glycolytic metabolism, greater fatty acid uptake, and decreased effector populations and cytokine production. At infection resolution, obese mice had lower numbers of naïve and central memory CD8+ T cell populations in the lungs.ConclusionDiet-induced obesity increases influenza virus pathogenesis through CD8+ T cell mediated metabolic reprogramming resulting in suppressed effector CD8+ T cell function.SummaryDiet-induced obesity impairs the metabolism of pulmonary CD8+ T cells resulting in reduced effector CD8+ T cells and cytokine production following primary influenza infection.

scholarly journals Predominant Clonal Accumulation of CD8+ T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

2010 ◽  
Vol 84 (6) ◽  
pp. 2774-2786 ◽  
Author(s):  
Hyun Seok Kang ◽  
Byung S. Kim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infection ◽  
Cell Receptor ◽  
High Avidity ◽  
Cell Repertoire ◽  
Cell Diversity ◽  
The Central Nervous System ◽  
And Function

ABSTRACT Induction of antigen-specific CD8+ T cells bearing a high-avidity T-cell receptor (TCR) is thought to be an important factor in antiviral and antitumor immune responses. However, the relationship between TCR diversity and functional avidity of epitope-specific CD8+ T cells accumulating in the central nervous system (CNS) during viral infection is unknown. Hence, analysis of T-cell diversity at the clonal level is important to understand the fate and function of virus-specific CD8+ T cells. In this study, we examined the Vβ diversity and avidity of CD8+ T cells specific to the predominant epitope (VP2121-130) of Theiler's murine encephalomyelitis virus. We found that Vβ6+ CD8+ T cells, associated with epitope specificity, predominantly expanded in the CNS during viral infection. Further investigations of antigen-specific Vβ6+ CD8+ T cells by CDR3 spectratyping and sequencing indicated that distinct T-cell clonotypes are preferentially increased in the CNS compared to the periphery. Among the epitope-specific Vβ6+ CD8+ T cells, MGX-Jβ1.1 motif-bearing cells, which could be found at a high precursor frequency in naïve mice, were expanded in the CNS and tightly associated with gamma interferon production. These T cells displayed moderate avidity for the cognate epitope rather than the high avidity normally observed in memory/effector T cells. Therefore, our findings provide new insights into the CD8+ T-cell repertoire during immune responses to viral infection in the CNS.

scholarly journals Restricting Tumor Lactate Metabolism using Dichloroacetate Improves T Cell Functions

2021 ◽  
Author(s):  
Hosein Rostamian ◽  
Mohammad Khakpoor-Kooshe ◽  
Leila Jafarzadeh ◽  
Elham Masoumi ◽  
Keyvan Fallah-Mehrjardi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cytokine Production ◽  
Redox System ◽  
T Cell Proliferation ◽  
And Function

Abstract Background:Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism.In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells. Result:We found that lactate could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactate by manipulatingglucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis. Conclusion:Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.

scholarly journals Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Hosein Rostamian ◽  
Mohammad Khakpoor-Koosheh ◽  
Leila Jafarzadeh ◽  
Elham Masoumi ◽  
Keyvan Fallah-Mehrjardi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cytokine Production ◽  
Redox System ◽  
T Cell Proliferation ◽  
And Function

Abstract Background Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells. Result We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis. Conclusion Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.

scholarly journals T Cell Immunity against Influenza: The Long Way from Animal Models Towards a Real-Life Universal Flu Vaccine

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 199
Author(s):  
Anna Schmidt ◽  
Dennis Lapuente
Keyword(s):  
T Cells ◽  
T Cell ◽  
Animal Models ◽  
Respiratory Tract ◽  
Memory T Cells ◽  
Real Life ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Flu Vaccine ◽  
Resident Memory T Cells

Current flu vaccines rely on the induction of strain-specific neutralizing antibodies, which leaves the population vulnerable to drifted seasonal or newly emerged pandemic strains. Therefore, universal flu vaccine approaches that induce broad immunity against conserved parts of influenza have top priority in research. Cross-reactive T cell responses, especially tissue-resident memory T cells in the respiratory tract, provide efficient heterologous immunity, and must therefore be a key component of universal flu vaccines. Here, we review recent findings about T cell-based flu immunity, with an emphasis on tissue-resident memory T cells in the respiratory tract of humans and different animal models. Furthermore, we provide an update on preclinical and clinical studies evaluating T cell-evoking flu vaccines, and discuss the implementation of T cell immunity in real-life vaccine policies.

scholarly journals Traditional Thai Massage Promoted Immunity in the Elderly via Attenuation of Senescent CD4+ T Cell Subsets: A Randomized Crossover Study

2021 ◽  
Vol 18 (6) ◽  
pp. 3210
Author(s):  
Kanda Sornkayasit ◽  
Amonrat Jumnainsong ◽  
Wisitsak Phoksawat ◽  
Wichai Eungpinichpong ◽  
Chanvit Leelayuwat
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crossover Study ◽  
Intracellular Cytokine Staining ◽  
The Elderly ◽  
Complementary Therapy ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
T Subsets ◽  
Randomized Crossover Study

The beneficial physiological effects of traditional Thai massage (TTM) have been previously documented. However, its effect on immune status, particularly in the elderly, has not been explored. This study aimed to investigate the effects of multiple rounds of TTM on senescent CD4+ T cell subsets in the elderly. The study recruited 12 volunteers (61–75 years), with senescent CD4+ T cell subsets, who received six weekly 1-h TTM sessions or rest, using a randomized controlled crossover study with a 30-day washout period. Flow cytometry analysis of surface markers and intracellular cytokine staining was performed. TTM could attenuate the senescent CD4+ T cell subsets, especially in CD4+28null NKG2D+ T cells (n = 12; p < 0.001). The participants were allocated into two groups (low < 2.75% or high ≥ 2.75%) depending on the number of CD4+28null NKG2D+ T cells. After receiving TTM over 6 sessions, the cell population of the high group had significantly decreased (p < 0.001), but the low group had no significant changes. In conclusion, multiple rounds of TTM may promote immunity through the attenuation of aberrant CD4+ T subsets. TTM may be provided as a complementary therapy to improve the immune system in elderly populations.

scholarly journals Chimeric non-antigen receptors in T cell-based cancer therapy

2021 ◽  
Vol 9 (8) ◽  
pp. e002628
Author(s):  
Jitao Guo ◽  
Andrew Kent ◽  
Eduardo Davila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Tumor Antigen ◽  
Cell Function ◽  
Antigen Recognition ◽  
Cancer Therapies ◽  
Antigen Receptors ◽  
Natural Ligands ◽  
And Function

Adoptively transferred T cell-based cancer therapies have shown incredible promise in treatment of various cancers. So far therapeutic strategies using T cells have focused on manipulation of the antigen-recognition machinery itself, such as through selective expression of tumor-antigen specific T cell receptors or engineered antigen-recognition chimeric antigen receptors (CARs). While several CARs have been approved for treatment of hematopoietic malignancies, this kind of therapy has been less successful in the treatment of solid tumors, in part due to lack of suitable tumor-specific targets, the immunosuppressive tumor microenvironment, and the inability of adoptively transferred cells to maintain their therapeutic potentials. It is critical for therapeutic T cells to overcome immunosuppressive environmental triggers, mediating balanced antitumor immunity without causing unwanted inflammation or autoimmunity. To address these hurdles, chimeric receptors with distinct signaling properties are being engineered to function as allies of tumor antigen-specific receptors, modulating unique aspects of T cell function without directly binding to antigen themselves. In this review, we focus on the design and function of these chimeric non-antigen receptors, which fall into three broad categories: ‘inhibitory-to-stimulatory’ switch receptors that bind natural ligands, enhanced stimulatory receptors that interact with natural ligands, and synthetic receptor-ligand pairs. Our intent is to offer detailed descriptions that will help readers to understand the structure and function of these receptors, as well as inspire development of additional novel synthetic receptors to improve T cell-based cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document