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

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.

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

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Michael M. Opata ◽  
Robin Stephens
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Chronic Infection ◽  
Malaria Infection ◽  
Memory T Cells ◽  
Cell Receptor ◽  
Blood Stage ◽  
Effector Memory ◽  
Plasmodium Chabaudi

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.

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

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.

scholarly journals Impaired Nk1.1 T Cell Development in Mice Transgenic for a T Cell Receptor β Chain Lacking the Large, Solvent-Exposed Cβ Fg Loop

1999 ◽  
Vol 190 (9) ◽  
pp. 1357-1362 ◽  
Author(s):  
Sylvie Degermann ◽  
Giuseppina Sollami ◽  
Klaus Karjalainen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Chain Structure ◽  
Small Population ◽  
Tcr Signaling ◽  
Α Chain ◽  
And Function ◽  
Β Chain

A striking feature of the T cell receptor (TCR) β chain structure is the large FG loop that protrudes freely into the solvent on the external face of the Cβ domain. We have already shown that a transgene-encoded Vβ8.2+ TCR β chain lacking the complete Cβ FG loop supports normal development and function of conventional α/β T cells. Thus, the FG loop is not absolutely necessary for TCR signaling. However, further analysis has revealed that a small population of α/β T cells coexpressing NK1.1 are severely depleted in these transgenic mice. The few remaining NK1.1 T cells have a normal phenotype but express very low levels of TCR. We find that the TCR Vβ8.2+ chain lacking the Cβ FG loop cannot pair efficiently with the invariant Vα14-Jα281 TCR α chain commonly expressed by this T cell family. Consequently, fewer NK1.1 T cells develop in these mice. Our results suggest that expression of the Vα14+ TCR α chain is particularly sensitive to TCR-β conformation. Development of NK1.1 T cells appears to need a TCR-β conformation dependent on the presence of the Cβ loop that is not necessarily required for assembly and function of TCRs on most α/β T cells.

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

2017 ◽  
Vol 7 (1) ◽  
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

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 Enhancing and inhibitory motifs have coevolved to regulate CD4 activity

2021 ◽  
Author(s):  
Mark S. Lee ◽  
Peter J. Tuohy ◽  
Caleb Kim ◽  
Katrina Lichauco ◽  
Heather L. Parrish ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Purifying Selection ◽  
Cell Receptor ◽  
Specific Information ◽  
Transmembrane Receptors ◽  
Peptide Antigens ◽  
And Function ◽  
Intracellular Domains

SUMMARYCD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+ T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

scholarly journals Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5560-5570 ◽  
Author(s):  
Karla R. Wiehagen ◽  
Evann Corbo ◽  
Michelle Schmidt ◽  
Haina Shin ◽  
E. John Wherry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Sh2 Domain ◽  
Normal Numbers ◽  
Tcr Signaling ◽  
Tcr Signals

Abstract The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. The SRC homology 2 (SH2)-domain–containing leukocyte protein of 76 kDa (SLP-76) is critical for proximal TCR-generated signaling. We used temporally mediated deletion of SLP-76 to interrupt tonic and activating TCR signals after clearance of the lymphocytic choriomeningitis virus (LCMV). SLP-76–dependent signals are required during the contraction phase of the immune response for the normal generation of CD8 memory precursor cells. Conversely, LCMV-specific memory CD8 T cells generated in the presence of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype, but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation, but are dispensable for memory CD8 T-cell persistence.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

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

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.

scholarly journals Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway

2020 ◽  
Vol 295 (8) ◽  
pp. 2239-2247 ◽  
Author(s):  
Jeoung-Eun Park ◽  
David D. Brand ◽  
Edward F. Rosloniec ◽  
Ae-Kyung Yi ◽  
John M. Stuart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cell Signaling ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Cell Signaling Pathway

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1–sufficient and –deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ζ chain of T-cell receptor–associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1–induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog–sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.

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