scholarly journals Decay-accelerating factor modulates induction of T cell immunity

2005 ◽  
Vol 201 (10) ◽  
pp. 1523-1530 ◽  
Author(s):  
Peter S. Heeger ◽  
Peter N. Lalli ◽  
Feng Lin ◽  
Anna Valujskikh ◽  
Jinbo Liu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Function ◽  
Alternative Pathway ◽  
T Cell Immunity ◽  
Host Cells ◽  
Decay Accelerating Factor ◽  
Local Alternative ◽  
Cell Immunity ◽  
Pathway Activation

Decay-accelerating factor (Daf) dissociates C3/C5 convertases that assemble on host cells and thereby prevents complement activation on their surfaces. We demonstrate that during primary T cell activation, the absence of Daf on antigen-presenting cells (APCs) and on T cells enhances T cell proliferation and augments the induced frequency of effector cells. The effect is factor D- and, at least in part, C5-dependent, indicating that local alternative pathway activation is essential. We show that cognate T cell–APC interactions are accompanied by rapid production of alternative pathway components and down-regulation of Daf expression. The findings argue that local alternative pathway activation and surface Daf protein function respectively as a costimulator and a negative modulator of T cell immunity and explain previously reported observations linking complement to T cell function. The results could have broad therapeutic implications for disorders in which T cell immunity is important.

Dendritic Cell-Induced T Cell Non-Responsiveness Is Mediated by FOXP3+ and TGF-beta+IL-10+ CD4+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3891-3891
Author(s):  
Zwi N. Berneman ◽  
Nathalie Cools ◽  
Viggo F.I. Van Tendeloo ◽  
Marc Lenjou ◽  
Griet Nijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Tgf Beta ◽  
Cell Immunity

Abstract Dendritic cells (DC), the professional antigen presenting cells of the immune system, exert important functions both in induction of T cell immunity as well as of tolerance. Previously, it was accepted that the main function of immature DC (iDC) in their in vivo steady state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. However, a growing body of experimental evidence now indicates that traditional DC maturation can no longer be used to distinguish between tolerogenic and immunogenic properties of DC. In this study, we compared the in vitro stimulatory capacity of immature DC (iDC), cytokine cocktail-matured DC (CC-mDC) and poly I:C-matured DC (pIC-mDC) in the absence and presence of antigen. All investigated DC types could induce at least 2 subsets of regulatory T cells. We observed a significant increase in both the number of functionally suppressive transforming growth factor (TGF)-beta+ interleukin (IL)-10+ T cells as well as of CD4+CD25+FOXP3+ T cells within DC/T cell co-cultures as compared to T cell cultures without DC. The induction of these regulatory T cells correlates with in vitro T cell non-responsiveness after co-culture with iDC and CC-mDC, while stimulation with pIC-mDC resulted in reproducible cytomegalovirus pp65 or influenza M1 matrix peptide-specific T cell activation as compared to control cultures in the absence of DC. In addition, the T cell non-responsiveness after stimulation with iDC was shown to be mediated by TGF-beta and IL-10. Moreover, the suppressive capacity of CD4+ T cells activated by iDC and CC-mDC was shown to be transferable when these CD4+ T cells were added to an established T cell response. In contrast, addition of CD4+ T cells stimulated by pIC-mDC made responder T cells refractory to their suppressive activity. In conclusion, we hypothesize that DC have a complementary role in inducing both regulatory T cells and effector T cells, where the final result of antigen-specific T cell activation will depend on the activation state of the DC. This emphasizes the need for proper DC activation when T cell immunity is the desired effect, especially when used in clinical trials.

scholarly journals Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

scholarly journals Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anabelle Visperas ◽  
Jeongsu Do ◽  
Booki Min
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Differentiation ◽  
T Cell Immunity ◽  
Immune Functions ◽  
Effector Cells ◽  
Cell Immunity

The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.

scholarly journals How does lenalidomide target the chronic lymphocytic leukemia microenvironment?

Blood ◽  
2014 ◽  
Vol 124 (14) ◽  
pp. 2184-2189 ◽  
Author(s):  
Arnon P. Kater ◽  
Sanne H. Tonino ◽  
Alexander Egle ◽  
Alan G. Ramsay
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Immunomodulatory Drug ◽  
Targeted Drug ◽  
Potential Use ◽  
Clinical Strategy

Abstract Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is an oral immunomodulatory drug that repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed.

scholarly journals Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen-presenting cells

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1008-1014 ◽  
Author(s):  
Chongyun Fang ◽  
Takashi Miwa ◽  
Wen-Chao Song
Keyword(s):  
T Cells ◽  
T Cell ◽  
Knockout Mice ◽  
Antigen Presenting Cells ◽  
T Cell Immunity ◽  
Decay Accelerating Factor ◽  
Cell Immunity ◽  
Complement Regulator ◽  
Antigen Presenting

Abstract Recent studies have indicated a role of complement in regulating T-cell immunity but the mechanism of action of complement in this process remains to be clarified. Here we studied mice deficient in decay-accelerating factor (DAF), a key membrane complement regulator whose deficiency led to increased complement-dependent T-cell immune responses in vivo. By crossing OT-II and OT-I T-cell receptor transgenic mice with DAF-knockout mice, we found that lack of DAF on T cells did not affect their responses to antigen stimulation. Similarly, lack of DAF on antigen-presenting cells (APCs) of naive mice did not alter their T-cell stimulating activity. In contrast, APCs from DAF-knockout mice treated with inflammatory stimuli were found to be more potent T-cell stimulators than cells from similarly treated wild-type mice. Acquisition of higher T-cell stimulating activity by APCs in challenged DAF-knockout mice required C3 and C5aR and was correlated with decreased surface PD-L1 and/or increased CD40 expression. These findings implied that DAF suppressed T-cell immunity as a complement regulator in the context of inflammation but did not play an intrinsic role on T cells or APCs. Collectively, our data suggest a systemic and indirect role of complement in T-cell immunity.

scholarly journals The GPR171 pathway suppresses T cell activation and limits antitumor immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuki Fujiwara ◽  
Robert J. Torphy ◽  
Yi Sun ◽  
Emily N. Miller ◽  
Felix Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
T Cell Immunity ◽  
Antigen Stimulation ◽  
Cell Immunity

AbstractThe recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

scholarly journals SARS-CoV-2 genome-wide mapping of CD8 T cell recognition reveals strong immunodominance and substantial CD8 T cell activation in COVID-19 patients

2020 ◽  
Author(s):  
Sunil Kumar Saini ◽  
Ditte Stampe Hersby ◽  
Tripti Tamhane ◽  
Helle Rus Povlsen ◽  
Susana Patricia Amaya Hernandez ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Disease ◽  
Protein A ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
High Exposure ◽  
Cell Immunity

SummaryTo understand the CD8+ T cell immunity related to viral protection and disease severity in COVID-19, we evaluated the complete SARS-CoV-2 genome (3141 MHC-I binding peptides) to identify immunogenic T cell epitopes, and determine the level of CD8+ T cell involvement using DNA-barcoded peptide-major histocompatibility complex (pMHC) multimers. COVID-19 patients showed strong T cell responses, with up to 25% of all CD8+ lymphocytes specific to SARS-CoV-2-derived immunodominant epitopes, derived from ORF1 (open reading frame 1), ORF3, and Nucleocapsid (N) protein. A strong signature of T cell activation was observed in COVID-19 patients, while no T cell activation was seen in the ‘non-exposed’ and ‘high exposure risk’ healthy donors. Interestingly, patients with severe disease displayed the largest T cell populations with a strong activation profile. These results will have important implications for understanding the T cell immunity to SARS-CoV-2 infection, and how T cell immunity might influence disease development.

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