scholarly journals Large Neutral Amino acid uptake and mTOR activation within CD4+ T cells coordinate Type 2 immunity and host resistance to Trichuris muris

2020 ◽  
Author(s):  
Maria Z Krauss ◽  
Kelly S Hayes ◽  
Ana Villegas-Mendez ◽  
Matthew R Hepworth ◽  
Linda V Sinclair ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Cd4 T Cells ◽  
High Dose ◽  
Acid Uptake ◽  
Large Neutral Amino Acid ◽  
Th2 Response ◽  
Trichuris Muris ◽  
Worm Expulsion

AbstractTrichuris trichiura (whipworm) is a gastrointestinal nematode that infects approximately 465 million people worldwide. T. muris is used as a tractable model for the human whipworm. In wild type mice, infection with a high dose of T. muris eggs leads to worm expulsion, which is dependent on a CD4+Th2 response and interleukin (IL-)13 production. It is known that T cells up-regulate glycolysis and uptake of substrates upon activation. The amino acid transporter SLC7A5 has been shown necessary for activation of mTORC1, a nutrient/energy/redox sensor critical for T cell differentiation into effector cells. We found that at the peak of the immune response to T. muris, mice lacking SLC7A5 in CD4+T cells have delayed worm expulsion, lower levels of IL-13, reduced pmTOR and glycolytic rates. However, at later stages of infection IL-13 levels partially recovered alongside resistance. The critical role of CD4+T cell metabolism per se and down-stream mTOR in CD4+T cells in resistance was shown in mice lacking mTOR in CD4+T cells, that failed to expel a high dose of parasites and developed chronic infection. Our study shows that mTOR is essential for effective functioning of T cells during whipworm infection and that deletion of Slc7a5 significantly delays worm clearance.

Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4053-4062 ◽  
Author(s):  
Andreas Heitger ◽  
Patricia Winklehner ◽  
Petra Obexer ◽  
Johannes Eder ◽  
Claudia Zelle-Rieser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
High Dose ◽  
T Helper

Impaired T-cell function after T-cell– depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4+CD45RA+ (naive) and of CD4+CD45RA− (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4+ T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4+CD45RA− cells, but, strikingly, also CD4+CD45RA+ cells, including samples in which CD4+CD45RA+ cells were more than 90/μL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4+CD45RA+cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4+ T cells (25% versus 6%) and also affected CD4+CD45RA+ cells (12% versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4+ cells and of CD4+CD45RA+ cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non–T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.

Differential regulation of T-cell growth by IL-2 and IL-15

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 600-608 ◽  
Author(s):  
Georgina H. Cornish ◽  
Linda V. Sinclair ◽  
Doreen A. Cantrell
Keyword(s):  
T Cells ◽  
Protein Synthesis ◽  
Amino Acid ◽  
T Cell ◽  
Cell Growth ◽  
De Novo ◽  
Cell Mass ◽  
Interleukin 2 ◽  
Amino Acid Uptake ◽  
Acid Uptake

Although interleukin 2 (IL-2) and IL-15 signal through the common gamma chain (γc) and through IL-2 receptor β–chain (CD122) subunits, they direct distinct physiologic and immunotherapeutic responses in T cells. The present study provides some insight into why IL-2 and IL-15 differentially regulate T-cell function by revealing that these cytokines are strikingly distinct in their ability to control protein synthesis and T-cell mass. IL-2 and IL-15 are shown to be equivalent mitogens for antigen-stimulated CD8+ T cells but not for equivalent growth factors. Antigen-primed T cells cannot autonomously maintain amino acid incorporation or de novo protein synthesis without exogenous cytokine stimulation. Both IL-2 and IL-15 induce amino acid uptake and protein synthesis in antigen-activated T cells; however, the IL-2 response is strikingly more potent than the IL-15 response. The differential action of IL-2 and IL-15 on amino acid uptake and protein synthesis is explained by temporal differences in signaling induced by these 2 cytokines. Hence, the present results show that cytokines that are equivalent mitogens can have different potency in terms of regulating protein synthesis and cell growth.

Induction and Capture of CD4+ Cytotoxic Adenoviral Specific T-Cells in Response to pan-DR Binding Adenoviral Epitopes; towards Immunotherapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3238-3238
Author(s):  
Lianne M. Haveman ◽  
Berent Prakken ◽  
Mark R. Klein ◽  
Salvo Albani ◽  
Marc Bierings
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Immunocompromised Host ◽  
Cytokine Profile ◽  
T Cell Epitopes ◽  
Double Positive ◽  
Th2 Response ◽  
Hexon Protein

Abstract In the immunocompromised host adenovirus may cause fatal infections, especially after stem cell transplantation. No effective antiviral medication exists for severe adenoviral infection. Adoptively transferring adenoviral (Adv) specific T-cells from the donor into the patient may be a promising treatment, but requires the identification of these cells. The aim of the study was to induce Adv-specific cells in response to recently detected pan-DR binding CD4+ T-cell epitopes of adenovirus serotype 5. Epitopes were selected by using a computer algorithm designed to predict HLA pan-DR binding T-cell epitopes. Peripheral blood mononuclear cells (PBMCs) of 26 healthy adults were incubated with 19 different 15-mer peptides. Proliferation expressed as Stimulation Index (SI) was determined. Five peptides with highest SI derived from fiber protein, E1B protein, hexon protein (2 peptides) and DNA-polymerase were selected. To induce Adv-specific T-cells PBMCs from healthy subjects were either cultured with complete inactivated adenovirus for 11 days and restimulated with the different peptides for 3 days (n=10) or directly cultured with the peptides for 7 days (n=10). The cytokine profile induced by these epitopes was determined with multiplex immunoassay (MIA). By using the T-cell capture (TCC) method1 and FACS-sorting it was possible to capture the Adv-specific T-cells for further characterization by PCR and FACS analysis. In comparison with medium and irrelevant Adv-peptides PBMCs cultured with the 5 selected Adv-peptides induced significant larger amounts of Adv-specific CD4+ T-cells and showed a predominant pro-inflammatory cytokine profile. This suggests that peptides are naturally processed. By using TCC Adv-peptide specific CD4+ T-cells were identified and sorted. The Adv-specific T-cells displayed a high expression of TGF-1b, IFNg and Tbet (Th1 response), but also in lesser extent GATA3 and IL10 (Th2 response). A majority of the CD4+ Adv-specific cells expressed perforin and granzyme B, indicating that these CD4+ T-cells play an essential role in adenoviral infections. The induction of a specific immune response to adenovirus and subsequent capture of the Adv-specific T-cells is an important step towards adoptive immunotherapy in case of Adv-infections in the immunocompromised host. Figure 1. Induction of adenoviral specific T-cells (CD4, CTB double positive cells) in response to Adv-peptides. 1A) Induction of CD4+ Adv-specific in response to medium stimulated PBMCs and 1B) in response to a peptide derived from hexon protein. Figure 1. Induction of adenoviral specific T-cells (CD4, CTB double positive cells) in response to Adv-peptides. 1A) Induction of CD4+ Adv-specific in response to medium stimulated PBMCs and 1B) in response to a peptide derived from hexon protein.

Critical Role of Neutrophils in Determining Antigen-Specific CD4+ T-Cell Tolerance In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3294-3294
Author(s):  
Fengdong Cheng ◽  
Pedro Horna ◽  
Hongwei Wang ◽  
Ildefonso Suarez ◽  
Xianhong Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
High Dose ◽  
Wild Type ◽  
Cognate Antigen ◽  
Induced Tolerance

Abstract In previous studies we have shown that Signal Transducer and Activator of Transcription 3 (STAT3) negatively regulates inflammatory responses in myeloid cells and plays a central role in determining immune activation versus immune tolerance of antigen-specific CD4+ T-cells. Indeed, in Stat3 knock out mice (LysMcre/Stat3flox/−) in which macrophages and neutrophils are devoid of Stat3, we found that in response to a tolerogenic stimulus (high dose peptide-induced tolerance or tumor-induced tolerance models) adoptively transferred antigen-specific CD4+ T-cells are not tolerized but instead are effectively primed as determined by their production of IL-2 and IFN-gamma in response to cognate antigen. Such an observation led us to investigate which cell population(s) is required for the priming effect observed in Stat3 KO mice. First, we used anti-Gr-1 antibody to deplete neutrophils in wild type BALB/c mice as well as Stat3 KO mice. Briefly, half the mice in each group were treated with 0.5mg of the antibody given i.p. every 3 days from day-3 until day +15. On day zero, all the mice were adoptively transferred with 2.5 x 106 naïve transgenic CD4+ T-cells specific for a MHC class II restricted epitope of hemaglutinin (HA). On day +2, animals received high dose of HA peptide (275 mcg) given i.v. Mice were sacrificed on day +15 and clonotypic T-cells were re-isolated from their spleens to assess their functional status following their in vivo exposure to this tolerogenic stimuli. A striking difference was observed in T-cells isolated from Stat3 KO mice with an intact neutrophil compartment (non-depleted) versus T-cells from anti-Gr-1 treated LysMcreStat3flox/− mice. Unlike T-cells from the former group in which priming was the functional outcome, clonotypic T-cells from LysMcreStat3flox/− mice depleted of neutrophils, were found to be anergic. Therefore, the T-cell priming effect observed in LysMcreStat3flox/− mice requires an intact neutrophil compartment given that in the absence of this population, tolerance not priming was the functional T-cell outcome. To gain insight into the potential mechanism(s) by which neutrophils devoid of Stat3 influence T-cell responses, we next analyzed the phenotypic and functional properties of neutrophils isolated from Stat3 KO mice and wild type controls. First, the lack of expression of MHC class II molecules by neutrophils from WT and KO mice made unlikely the possibility that neutrophils devoid of Stat3 could directly present antigen to CD4+ T-cells. However, when neutrophils from Stat3−/− conditional mice were added to macrophages monolayers in vitro, the antigen-presenting capabilities of macrophages was significantly enhanced as determined by the increased production of IL-2 and IFN-gamma by antigen-specific T-cells encountering cognate antigen in these APCs. Furthermore, macrophages cultured in vitro with neutrophils from Stat3−/− conditional mice were able to restore the responsiveness of tolerant CD4+ T-cells. This effect that was not observed when tolerized T-cells encountered cognate antigen in macrophages incubated with neutrophils from wild type mice. Trans-well experiments demonstrated that the regulatory effect of neutrophils upon APCs function required cell-cell contact. Taken together, we have unveiled a previously unrecognized role of neutrophils in determining the functional outcome of antigen-specific T-cell responses, effect that is dependent upon the interaction of neutrophils with antigen-presenting cells.

Evidence for naive T-cell repopulation despite thymus irradiation after autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+ selection and age

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1891-1897 ◽  
Author(s):  
Marion Malphettes ◽  
Guislaine Carcelain ◽  
Pierre Saint-Mezard ◽  
Véronique Leblond ◽  
Hester Korthals Altes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Autologous Transplantation ◽  
High Dose ◽  
T Cell Reconstitution ◽  
Unselected Group ◽  
Cell Repopulation

Immunodeficiency following autologous CD34+-purified peripheral blood stem cell (PBSC) transplantation could be related to T-cell depletion of the graft or impaired T-cell reconstitution due to thymus irradiation. Aiming to assess the role of irradiated thymus in T-cell repopulation, we studied 32 adults with multiple myeloma, randomly assigned to receive high-dose therapy including total body irradiation (TBI) followed by autologous transplantation with either unselected or CD34+-selected PBSCs. The median number of reinfused CD3+ cells was lower in the selected group (0.03 versus 14 × 106/kg; P = .002). Lymphocyte subset counts were evaluated from month 3 to 24 after grafting. Naive CD4+ T cells were characterized both by phenotype and by quantification of T-cell receptor rearrangement excision circles (TRECs). The reconstitution of CD3+ and CD4+ T cells was significantly delayed in the CD34+-selected group, but eventually led to counts similar to those found in the unselected group after month 12. Mechanism of reconstitution differed, however, between both groups. Indeed, a marked increase in the naive CD62L+CD45RA+CD4+subset was observed in the selected group, but not in the unselected group in which half of the CD45RA+CD4+ T cells appear to be CD62L−. Age was identified as an independent adverse factor for CD4+ and CD62L+CD45RA+CD4+ T-cell reconstitution. Our results provide evidence that infusing PBSCs depleted of T cells after TBI in adults delays T-cell reconstitution but accelerates thymic regeneration.

scholarly journals IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform

2010 ◽  
Vol 207 (7) ◽  
pp. 1421-1433 ◽  
Author(s):  
Patricia A. Darrah ◽  
Sonia T. Hegde ◽  
Dipti T. Patel ◽  
Ross W. B. Lindsay ◽  
Linda Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
High Dose ◽  
Th1 Cells ◽  
Protective Capacity ◽  
Th1 Response ◽  
Ifn Γ

The quality of a Th1 response can be a prospective correlate of vaccine-mediated protection against certain intracellular pathogens. Using two distinct vaccine platforms, we evaluate the influence of interleukin (IL) 10 production on the magnitude, quality, and protective capacity of CD4+ T cell responses in the mouse model of Leishmania major infection. Multiparameter flow cytometry was used to delineate the CD4+ T cell production of interferon (IFN) γ, IL-2, tumor necrosis factor (TNF), and IL-10 (or combinations thereof) after vaccination. Immunization with a high dose of adenovirus (ADV) expressing leishmanial proteins (MML-ADV) elicited a limited proportion of multifunctional IFN-γ+IL-2+TNF+ Th1 cells, a high frequency of IL-10–producing CD4+ T cells, and did not protect against subsequent challenge. Surprisingly, in the absence of IL-10, there was no change in the magnitude, quality, or protective capacity of the Th1 response elicited by high-dose MML-ADV. In contrast, after immunization with MML protein and CpG (MML + CpG), IL-10 limited the production of IL-12 by DCs in vivo, thereby decreasing the generation of multifunctional Th1 cells. Consequently, three immunizations with MML + CpG were required for full protection. However, inhibiting IL-10 at the time of immunization enhanced the magnitude and quality of the Th1 response sufficiently to mediate protection after only a single immunization. Overall, we delineate distinct mechanisms by which vaccines elicit protective Th1 responses and underscore the importance of multifunctional CD4+ T cells.

scholarly journals CD4 T Cells and Major Histocompatibility Complex Class II Expression Influence Worm Expulsion and Increased Intestinal Muscle Contraction during Trichinella spiralisInfection

1999 ◽  
Vol 67 (11) ◽  
pp. 6090-6097 ◽  
Author(s):  
Bruce A. Vallance ◽  
Francesca Galeazzi ◽  
Stephen M. Collins ◽  
Denis P. Snider
Keyword(s):  
T Cells ◽  
T Cell ◽  
Muscle Contraction ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Worm Expulsion ◽  
Deficient Mice

ABSTRACT Expulsion of intestinal nematode parasites and the associated increased contraction by intestinal muscle are T cell dependent, since both are attenuated in athymic rodents. The CD4 T-cell subset has been strongly associated with worm expulsion; however, the relationship between these cells, antigen presentation, and worm expulsion is not definitive and the role of these factors in intestinal muscle hypercontractility has not been defined. We infected C57BL/6, athymic, CD4-deficient, CD8α-deficient, and major histocompatibility complex class II (MHC II)-deficient (C2d) mice with Trichinella spiralis larvae. We examined intestinal worm numbers, longitudinal muscle contraction, and MHC II expression. Numerous MHC II-positive cells were identified within the muscularis externa of infected but not uninfected C57BL/6 mice. C57BL/6 and CD8α-deficient mice developed large increases in muscle contraction, expelling the parasite by day 21. Athymic and C2d mice exhibited much smaller increases in muscle contraction and delayed parasite expulsion. CD4-deficient mice exhibited intermediate levels of muscle contraction and delayed parasite expulsion. To further examine the role of MHC II and CD4 T cells, we irradiated C2d mice and reconstituted them with C57BL/6 bone marrow alone or with C57BL/6 CD4 T cells. C57BL/6 bone marrow alone did not affect muscle function or worm expulsion in recipient C2d mice. Partial CD4 T-cell reconstitution was sufficient to restore increased muscle contraction but not worm expulsion. Thus, hematopoietic MHC II expression alone is insufficient for the development of muscle hypercontractility and worm expulsion, but the addition of even small numbers of CD4 T cells was sufficient to induce intestinal muscle pathophysiology.

scholarly journals Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Stephanie M. Dillon ◽  
Tezha A. Thompson ◽  
Allison J. Christians ◽  
Martin D. McCarter ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Older Persons ◽  
Age Groups ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

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