Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

ABSTRACT Exposure to blood-stage malaria infection is often persistent, leading to generation of CD4 effector and effector memory T cells that contribute to protection. We showed previously that chronic exposure to blood-stage Plasmodium chabaudi offers the best protection from parasitemia and pathology in reinfection cases, correlating with an increase in Th1 cells. Although much is known about the features of resting or exhausted memory T cells (Tmem), little is known about the functional capacities of chronically stimulated but protective T cells. To determine the functional capacity of CD4 T cells generated by chronic infection upon reexposure to parasite, we compared their responses to known features of classical Tmem. The numbers of cytokine-producing T cells increased following infection in the polyclonal populations, suggesting an increase in pathogen-specific T cells. Malaria antigen-specific B5 T cell receptor (TCR) transgenic (Tg) T cells from chronic infection proliferated on reinfection and were highly sensitive to TCR stimulation without costimulation, as shown for Tmem in acute stimulations. However, B5 Tmem did not accumulate more than naive B5 T cells in vivo or in vitro and became apoptotic. Failure to accumulate was partly the result of chronic stimulation, since eliminating persistent parasites before reinfection slightly increased the accumulation of B5 Tg T cells upon reinfection. The levels of specific gamma interferon-positive, interleukin-10-positive T cells, which protect animals from pathology, increased after malaria infection. These data demonstrate that although chronic infection generates a protective T cell population with increased TCR sensitivity and cytokine production, they do not reexpand upon reexposure due to increased apoptosis.

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Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain TRM Formation and Function

Frontiers in Immunology ◽

10.3389/fimmu.2020.624144 ◽

2021 ◽

Vol 11 ◽

Author(s):

Colleen S. Netherby-Winslow ◽

Katelyn N. Ayers ◽

Aron E. Lukacher

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Memory T Cells ◽

Infectious Agent ◽

Cell Receptor ◽

Effector Memory ◽

Tcr Signaling ◽

And Function ◽

Barrier Tissues

Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRM are transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRM are governed by a contextual milieu that balances TRM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRM phenotype and function, and discuss the contribution of TRM to promoting protective immune responses in situ while maintaining tissue homeostasis.

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White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

10.1101/19005934 ◽

2019 ◽

Author(s):

Julia Sbierski-Kind ◽

Knut Mai ◽

Jonas Kath ◽

Anke Jurisch ◽

Mathias Streitz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Immune Cell ◽

Memory T Cells ◽

Cell Receptor ◽

Effector Memory ◽

Short Term ◽

Effector Memory T Cells ◽

Cytokine Levels

AbstractObesity is a growing global health problem due to its association with chronic low-grade inflammation contributing to metabolic complications. Multiple studies indicate that white adipose tissue (WAT) inflammation can promote type 2 diabetes. However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal obese women who either underwent CR for three months followed by a 4 weeks phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and subcutaneous WAT (SAT) (n=21). The T cell receptor repertoire was analyzed by next generation sequencing (n=20) and cytokine levels were determined in SAT (n=22). Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp and then correlated to immune cell subsets. We found that insulin resistance (IR) correlates significantly with a shift towards the memory T cell compartment in SAT. Among various T cell subsets, predominantly CD8+ effector memory T cells were associated with obesity-related IR. Interestingly, T cell receptor analysis revealed a diverse repertoire in SAT arguing against an antigen-driven intra-SAT expansion of effector memory T cells. Surprisingly, neither inflammatory cytokine levels nor leucocyte subpopulations were significantly altered upon CR. Our findings demonstrate the accumulation of effector memory T cells in obese SAT contributing to chronic inflammation. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR induced weight loss.

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Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals

Scientific Reports ◽

10.1038/s41598-017-03855-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 22

Author(s):

Takahiko Miyama ◽

Takakazu Kawase ◽

Kazutaka Kitaura ◽

Ren Chishaki ◽

Masashi Shibata ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Memory T Cells ◽

Cell Receptor

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P083 Characterisation of T-cell receptor repertoire patterns of circulating a4b7 positive memory T cells in ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.212 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S176-S177

Author(s):

A Gamliel ◽

L Werner ◽

N Salamon ◽

M Pinsker ◽

B Weiss ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Memory T Cells ◽

Cell Receptor ◽

Control Subjects ◽

Receptor Repertoire ◽

Negative Memory ◽

T Cell Receptor Repertoire ◽

Cell Receptor Repertoire

Abstract Background Memory T cells play an important role in mediating inflammatory responses in IBD. The integrin a4b7 is highly expressed on activated T cells, and is thought to direct homing of lymphocytes to the intestine, following its binding to MADCAM-1 expressed exclusively on intestinal endothelial cells. Since UC is characterised by oligoclonal expansion of specific T-cell clonotypes, we hypothesised that circulating memory T cells with gut-homing potential would exhibit unique T-cell receptor repertoire features. Methods Peripheral blood mononuclear cells were collected from 5 control subjects and 6 pediatric patients with active UC. Following CD3 MACS sorting cells were FACS sorted into a4b7 positive and a4b7 negative CD3+CD45RO+ memory T cells. DNA was Isolated from each subset and subjected to next-generation sequencing of the TCRB. This high-throughput platform employs massive parallel sequencing to process millions of rearranged T-cell receptor (TCR) products simultaneously, and permits an in-depth analysis of individual TCRs at the nucleotide level. Comparisons of different indices of diversity, CDR3 length and clonal biochemical characteristics were performed between a4b7 positive and a4b7 negative populations for each subject, and between controls and UC patients. Results PBMCs were isolated from active UC patients during endoscopic assessment. Four patients had a Mayo endoscopic score of 2, and two patients had a score of 1. Only one patient was treated with an immunosuppressive medication (azathioprine), and five out of six patients were treated with 5ASAs. Percentages of memory T cells (43.8 ± 12.3% vs. 32.2 ± 13.1%, p = 0.17) and a4b7 positive T cells (33.6 ± 15.7% vs. 36.0 ± 17.6%, p = 0.81) were comparable between controls and UC patients. Interestingly, a4b7 positive memory T cells displayed a polyclonal distribution, in both control subjects and in UC patients, without expansion of specific clones. Different indices of diversity, including shanon’s H, clonality index and entropy, were similar among controls and patients, both for a4b7 positive and a4b7 negative populations. Finally, clonal overlap between a4b7 positive and a4b7 negative memory T cells, for each subject was high, ranging between 30–50% for controls and 27–48% for UC patients. Conclusion a4b7 expressing memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active UC, with high rates of overlap with a4b7 negative memory T cells. Our study, along with additional recent reports, challenge the dogma of the importance of a4b7 expression for T-cell migration to the gut, and may suggest that vedolizumab’s suppresses intestinal inflammation by blocking the trafficking of innate immune subsets.

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Human T-cell receptor (TCR) alpha/beta + CD4-CD8- T cells express oligoclonal TCRs, share junctional motifs across TCR V beta-gene families, and phenotypically resemble memory T cells.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.24.11787 ◽

1993 ◽

Vol 90 (24) ◽

pp. 11787-11791 ◽

Cited By ~ 28

Author(s):

E. G. Brooks ◽

S. P. Balk ◽

K. Aupeix ◽

M. Colonna ◽

J. L. Strominger ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Memory T Cells ◽

Gene Families ◽

Cell Receptor ◽

Human T Cell ◽

Alpha Beta ◽

Beta Gene

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Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination

Science Translational Medicine ◽

10.1126/scitranslmed.aaf1725 ◽

2016 ◽

Vol 8 (332) ◽

pp. 332ra46-332ra46 ◽

Cited By ~ 34

Author(s):

Qian Qi ◽

Mary M. Cavanagh ◽

Sabine Le Saux ◽

Hong NamKoong ◽

Chulwoo Kim ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Chronic Infection ◽

Cell Receptor ◽

Control Mechanisms ◽

Cell Repertoire ◽

T Cell Clones ◽

Varicella Zoster ◽

Cell Clones

Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen–reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

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TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

10.1101/616441 ◽

2019 ◽

Author(s):

Xu Jiang ◽

Shi-yu Wang ◽

Chen Zhou ◽

Jing-hua Wu ◽

Yu-hao Jiao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Th17 Cells ◽

Cell Receptor ◽

T Cell Subsets ◽

Effector Memory ◽

Systemic Autoimmune Disease ◽

Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

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Quantitative Analysis of T-Cell Receptor β Variable-Gene Usage in Cutaneous Late-Phase Reactions: Implications for T-Lymphocyte Recruitment in Cutaneous Inflammation

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.6.1.85-88.1999 ◽

1999 ◽

Vol 6 (1) ◽

pp. 85-88 ◽

Cited By ~ 3

Author(s):

Stuart R. Lessin ◽

Bernice M. Benoit ◽

Guoqing Li ◽

Ann Moskovitz ◽

Burton Zweiman

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Lymphocyte ◽

Memory T Cells ◽

Immunoglobulin E ◽

Late Phase ◽

Cell Receptor ◽

T Cell Subsets ◽

Variable Gene

ABSTRACT To determine if functionally distinct T-lymphocyte (T cell) subsets accumulate in late-phase immunoglobulin E-mediated reactions (LPR), we quantitatively analyzed the immunophenotype and the T-cell receptor β variable-gene (Vβ) repertoire of T cells in cutaneous LPR. Peripheral blood and skin biopsies were obtained 6 or 24 h after sensitive subjects were challenged with intradermal injections of grass pollen allergen (Ag) and control (C) solution. The frequency of cells expressing CD3, CD4, CD8, CD45RO, and CD25/mm2 was determined by immunohistochemistry in nine subjects. Vβ usage was assessed by reverse transcription-PCR in five of nine subjects. A significantly greater frequency of CD3+ and CD45RO+ (memory) T cells was detected in Ag sites than in C sites at 24 h after challenge but not at 6 h. The frequency of activated (CD25+) and helper (CD4+) T cells appeared to be increased in Ag sites as well, though not significantly. Vβ6 was the most commonly expressed Vβ detected in Ag sites, but it was also detected in accompanying C sites. Vβ2 was the most commonly expressed Vβ detected in C sites. Sequence analysis in one case revealed Vβ expression in a 6-h Ag site to be essentially polyclonal. Our findings suggest that memory T cells with Vβ expression similar to that in normal skin accumulate in developing cutaneous LPR. The limited usage of Vβ suggests a preferential recruitment or retention of reactive T cells from an endogenous subset of skin-homing T cells with its own skewed Vβ repertoire.

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Transcriptional programming and T cell receptor repertoires distinguish human lung and lymph node memory T cells

Communications Biology ◽

10.1038/s42003-019-0657-2 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 2

Author(s):

Nathan Schoettler ◽

Cara L Hrusch ◽

Kelly M Blaine ◽

Anne I Sperling ◽

Carole Ober

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

T Cell Receptor ◽

Human Lung ◽

Memory T Cells ◽

Cell Receptor ◽

T Cell Subsets ◽

Memory T Cell ◽

Specific Memory

Abstract Antigen-specific memory T cells persist for years after exposure to a pathogen and provide effective recall responses. Many memory T cell subsets have been identified and differ in abundance throughout tissues. This study focused on CD4 and CD8 memory T cells from paired human lung and lung draining lymph node (LDLN) samples and identified substantial differences in the transcriptional landscape of these subsets, including higher expression of an array of innate immune receptors in lung T cells which were further validated by flow cytometry. Using T cell receptor analysis, we determined the clonal overlap between memory T cell subsets within the lung and within the LDLN, and this was greater than the clonal overlap observed between memory T cell subsets compared across tissues. Our results suggest that lung and LDLN memory T cells originate from different precursor pools, recognize distinct antigens and likely have separate roles in immune responses.

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