scholarly journals PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype

PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001199
Author(s):  
Giorgia Fanelli ◽  
Marco Romano ◽  
Estefania Nova-Lamperti ◽  
Mariana Werner Sunderland ◽  
Alessandra Nerviani ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Memory T Cells ◽  
Human Memory ◽  
Cell Receptor ◽  
Erk Signaling ◽  
Erk Phosphorylation ◽  
Programmed Death ◽  
Memory Cd4 T Cells ◽  
Regulatory Phenotype

Programmed death cell receptor 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA−CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.

scholarly journals Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor

2001 ◽  
Vol 194 (6) ◽  
pp. 719-732 ◽  
Author(s):  
Saied Mirshahidi ◽  
Ching-Tai Huang ◽  
Scheherazade Sadegh-Nasseri
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Critical Role ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Memory Cd4 T Cells

Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4+ T cells can be rendered anergic by presentation of low densities of agonist peptide–major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2–reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti–CTLA-4 blocking antibody restored anergy in vivo.

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

Enhanced Infiltration of Central Memory T Cells to the Lung Tissue during Allergic Lung Inflammation

2021 ◽  
pp. 1-15
Author(s):  
Mashael Alabed ◽  
Asma Sultana Shaik ◽  
Narjes Saheb Sharif-Askari ◽  
Fatemeh Saheb Sharif-Askari ◽  
Shirin Hafezi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Differential Distribution ◽  
Allergic Lung Inflammation

Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (T<sub>EM</sub>) and central memory (T<sub>CM</sub>) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent T<sub>CM</sub> phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of T<sub>CM</sub> cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of T<sub>CM</sub> cells to lung tissues during allergic airway inflammation. Expression levels of T<sub>CM</sub> homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased T<sub>CM</sub> infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of T<sub>CM</sub> profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for T<sub>EM</sub> cells during lung inflammation, suggesting a shift for T<sub>EM</sub> into the T<sub>CM</sub> state. To our knowledge, this is the first study to report an increased infiltration of T<sub>CM</sub> cells into inflamed lung tissues and to suggest differentiation of T<sub>EM</sub> to T<sub>CM</sub> cells in these tissues. Therapeutic interference at T<sub>CM</sub> infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.

scholarly journals In vitro maintaining of CD4+ central and effector memory cells in normal and inflammatory conditions

2020 ◽  
Vol 22 (5) ◽  
pp. 837-846
Author(s):  
E. A. Blinova ◽  
A. V. Kolerova ◽  
V. E. Balyasnikov ◽  
V. A. Kozlov
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Cell Receptor ◽  
Whole Body ◽  
Effector Memory ◽  
Adherent Cell ◽  
Memory Cells ◽  
Inflammatory Conditions ◽  
Low Sensitivity

IL-7 is a key factor for the survival and maintenance of CD4+ central (Tcm) and effector (Tem) memory cells in the whole body. In many autoimmune diseases, an elevated level of IL-7 is detected in blood serum and at the site of inflammation, thus suggesting participation of this homeostatic factor in the survival of memory T cells, including auto-reactive clones, in inflammatory disorders. The aim of the study was to investigate the mechanisms of maintaining CD4+ memory T cells under normal and inflammatory conditions. We developed an in vitro model of inflammation, based on induction of pro-inflammatory cytokines, and then evaluated the effects of IL-7 upon purified sorted populations of CD4+Tcm and Tem under normal conditions and in vitro inflammatory model. IL-7 treatment promoted maintenance of CD4+Tcm phenotype in all variants of cultures. In the absence of contact with adherent cell fraction, the IL-7-induced proliferation of Tcm and Tem was slightly reduced, both under normal and inflammatory conditions, thus suggesting low sensitivity of memory T cells to contacts with MHC, and, probably, a requirement for additional signals to provide complete stimulation with IL-7. The last suggestion is also supported by data about CD127 and CD132 expression, i.e., in the absence of contact with MHC, the proportion of CD127+CD132+ cells was decreased in both subpopulations of CD4+ memory cells. Upon in vitro cultures, IL-7 contributed to decreased expression of CD127, and increased expression of CD132 on CD4+Tcm and Tem. We have evaluated the CD4+Tcm and Tem populations by affinity of T cell receptor (TCR), using the level of CD5 expression. Т cells with high TCR affinity for self-antigens are known to have higher expression of CD5. In comparison to Tem, the Tcm contained more CD5high cells. In cultures, IL-7 promoted a high level of CD5 expression on Tcm, which was comparable to levels observed in peripheral blood cells. High CD5 expression on Tem was observed after stimulation with IL-7 in the in vitro inflammatory model. In the absence of contact with MHC, the number of CD5high cells decreased among CD4+Tem and Tcm. Thus, CD4+Tcm cells with high affinity for autologous antigens are probably dependent on the presence of homeostatic factors, in particular, IL-7, and contacts with antigen-presenting cells (APCs). Under conditions of inflammation, no changes were revealed in the mechanism of maintaining CD4+Tcm, in contrast to CD4+Tem. Being less dependent on IL-7 under normal conditions, CD4+CD5highTem are accumulated in the presence of IL-7 under in vitro inflammatory conditions.

Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation

1989 ◽  
Vol 19 (5) ◽  
pp. 803-808 ◽  
Author(s):  
Martin E. Sanders ◽  
Malegapuru W. Makgoba ◽  
Carl H. June ◽  
Howard A. Young ◽  
Stephen Shaw
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Human Memory

scholarly journals Ex Vivo Phenotype and Frequency of Influenza Virus-Specific CD4 Memory T Cells

2004 ◽  
Vol 78 (13) ◽  
pp. 7284-7287 ◽  
Author(s):  
Michaela Lucas ◽  
Cheryl L. Day ◽  
Jessica R. Wyer ◽  
Sharon L. Cunliffe ◽  
Andrew Loughry ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Class Ii ◽  
Low Frequencies ◽  
Tetramer Staining ◽  
Specific Memory ◽  
Memory Cd4 T Cells

ABSTRACT Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct “central memory” CD62L+ phenotype.

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