scholarly journals TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

2009 ◽  
Vol 206 (10) ◽  
pp. 2111-2119 ◽  
Author(s):  
Ning Lu ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Kazuhiko Arima ◽  
Shino Hanabuchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Th2 Differentiation

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.

scholarly journals Bone marrow–based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 612-621 ◽  
Author(s):  
Mirko Paiardini ◽  
Barbara Cervasi ◽  
Jessica C. Engram ◽  
Shari N. Gordon ◽  
Nichole R. Klatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Homeostatic Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

AbstractBone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8+ T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)–infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineage-specific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4+ or CD8+ T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIV-infected SMs, but not RMs, the level of proliferation of BM-based CD4+ T cells is higher than that of circulating CD4+ T cells. Interestingly, limited BM-based CD4+ T-cell proliferation was found in SIV-infected SMs with low CD4+ T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4+ T-cell proliferation in determining the benign nature of natural SIV infection of SMs.

The Elevated Ratio of Peripheral Blood CD27−CD4+ T Cells in Patients Received Allogeneic Stem Cell Transplantation Implies Altered T Cell Homeostasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1413-1413
Author(s):  
Akiko Fukunaga ◽  
Takayuki Ishikawa ◽  
Takero Shindo ◽  
Sumiko Takao ◽  
Toshiyuki Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Effector Cells

Abstract One of the major problems following allogeneic stem cell transplantation (allo-SCT) is the inability to reconstitute an adequate immune system for an extended period. T-cell reconstitution is also delayed for years, especially in CD4+ T cells. In addition to impaired thymic function, shortened Naive T cell survival due to altered T cell homeostasis is reported to be responsible for delayed immune reconstitution. To further investigate the mechanisms of delayed immune recovery after allo-SCT, we focused on the frequencies of effector CD4+ T cells, because according to the previous reports, progressive linear differentiation model of CD4+ T cell predicts the accumulation of terminally differentiated effector cells when transition from naïve to memory T cells and memory to effector cells are accelerated. By flowcytometric analyses we confirmed that CD27−CD4+ T cells from allo-SCT recipients uniformly express CD95, with negative expression of CCR7 and CD62L. They also produce g-interferon (IFNg) in response to the immobilized anti-CD3 and soluble anti-CD28 stimulation, which is consistent with previous reports insisting that CD27−CD4+ T cells are functionally differentiated effector T cells. Measuring the ratio of CD27−CD4+ T cells among CD4+ T cells revealed that, although healthy donors and patients received allo-SCT within a year had comparable CD27+CD4+T-cell rate (90% vs. 83%, P=0.4436), significantly decreased rate was observed in patients transplanted more than 1 year before (55% vs. 83%, P=0.0005). The ratio of CD27+CD4+ T cells kept low during the first 5 years after allo-SCT, and then it slowly begun to increase. In addition, in patients who received stem cell grafts more than 1 year before, the ratio of CD27+CD4+ T cells were significantly higher in patients transplanted from HLA-matched siblings than in those received unrelated grafts (69% vs. 42%, P=0.0002). Other factors, such as stem cell source (BM or PBSC), patient age, and the presence of chronic GVHD did not influence the ratio of CD27+CD4+ T cells. To further investigate the characteristics of CD27−CD4+ T cells in post-transplant periods, peripheral CD4+ T cells from patients who had received allo-SCT more than 1 year before as well as healthy volunteers were sorted into CD27− and CD27+ fractions, stained with CFSE, and stimulated with immobilized anti-CD3 and soluble anti-CD28 antibodies. CD27−CD4+ T cells proliferated more vigorously at 3 days after stimulation, though after another 2-day culture, there was no difference in cell divisions between both cell groups. In addition, CD27+ cells from transplanted patients lost their expression more frequently than those from volunteers, while none of the CD27− cells stored its expression. The fact of one-way transition from CD27+ to CD27− also supported that CD27−CD4+ T cells are terminally differentiated T cells. The finding that the frequencies of CD27−CD4+ T cells begin to elevate at 1 year after allo-SCT indicates that T cells infused with allograft do not easily lose the surface expression of CD27, while T cells derived from donor’s stem cells do. Considering the fact that ratio of CD27−CD4+ T cells is much higher in recipients of unrelated grafts, and it gradually begin to decrease at 5 years after allo-SCT, the increased ratio of CD27−CD4+ T cells may reflect altered T cell homeostasis. The serial monitoring of the ratio of CD27−CD4+ T cells after allo-SCT may be useful in evaluating immune reconstitution status.

The Effects of Stimulation with PMA/Ionomycin on CD4+ T cell Proliferation and Surface CD4 Molecule Modulation of Patients with LRBA Deficiency and CVID with the Unsolved Genetic Defect

2021 ◽  
Vol 21 ◽  
Author(s):  
Fereshte Salami ◽  
Sahar Shariati ◽  
Seyed Erfan Rasouli ◽  
Samaneh Delavari ◽  
Marziyeh Tavakol ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Healthy Individuals ◽  
Cell Frequency ◽  
Before And After ◽  
Lrba Deficiency

Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality. Methods: The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION. Results: The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation. Conclusion : Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.

scholarly journals Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

2010 ◽  
Vol 277 (1701) ◽  
pp. 3773-3781 ◽  
Author(s):  
Ming Liang Chan ◽  
Janka Petravic ◽  
Alexandra M. Ortiz ◽  
Jessica Engram ◽  
Mirko Paiardini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Number ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Proliferating Cells ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

scholarly journals A role for TSLP in the development of inflammation in an asthma model

2005 ◽  
Vol 202 (6) ◽  
pp. 829-839 ◽  
Author(s):  
Amin Al-Shami ◽  
Rosanne Spolski ◽  
John Kelly ◽  
Andrea Keane-Myers ◽  
Warren J. Leonard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Interferon Γ ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Asthma Model ◽  
Memory Cd4 T Cells ◽  
Th2 Differentiation

Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis. We now demonstrate that TSLP is required to mount a normal CD4+ T cell–mediated inflammatory response. TSLP acts directly on naive, but not, memory CD4+ T cells, and promotes their proliferation in response to antigen. In addition, TSLP exerts an effect indirectly through DCs to promote Th2 differentiation of CD4+ T cells. Correspondingly, TSLP receptor (TSLPR) knockout (KO) mice exhibit strong Th1 responses, with high levels of interleukin (IL)-12, interferon-γ, and immunoglobulin (Ig) G2a, but low production of IL-4, -5, -10, -13, and IgE; moreover, CD4+ T cells from these animals proliferate less well in response to antigen. Furthermore, TSLPR KO mice fail to develop an inflammatory lung response to inhaled antigen unless supplemented with wild-type CD4+ T cells. This underscores an important role for this cytokine in the development of inflammatory and/or allergic responses in vivo.

scholarly journals Mesenchymal Stromal Cells from Osteoarthritic Synovium Are a Distinct Population Compared to Their Bone-Marrow Counterparts regarding Surface Marker Distribution and Immunomodulation of Allogeneic CD4+ T-Cell Cultures

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Sebastien Hagmann ◽  
Claudia Rimmele ◽  
Florin Bucur ◽  
Thomas Dreher ◽  
Felix Zeifang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cd4 T Cells ◽  
Surface Marker ◽  
Cd4 T Cell ◽  
T Cell Proliferation

Introduction. The participation of an inflammatory joint milieu has been described in osteoarthritis (OA) pathogenesis. Mesenchymal stromal cells (MSCs) play an important role in modulating inflammatory processes. Based on previous studies in an allogeneic T-cell coculture model, we aimed at further determining the role of synovial MSCs in OA pathogenesis.Methods. Bone-marrow (BM) and synovial membrane (SM) MSCs from hip joints of late stage OA patients and CD4+ T-cells from healthy donors were analysed regarding surface marker expression before and after coculture. Proliferation upon CD3/CD28 stimulation and cytokine analyses were compared between MSCs.Results. SM-MSCs differed from BM-MSCs in several surface markers and their osteogenic differentiation potential. Cocultures of both MSCs with CD4+ T-cells resulted in recruitment of CD45RA+ FoxP3+ regulatory T-cells. Upon stimulation, only SM-MSCs suppressed CD4+ T-cell proliferation, while both SM-MSCs and BM-MSCs modified cytokine profiles through suppressing IL-2 and TNF-αas well as increasing IL-6 secretion.Conclusions. Synovial MSCs from OA joints are a unique fraction that can be distinguished from their bone-marrow derived counterparts. Their unique ability to suppress CD3/CD28 induced CD4+ T-cell proliferation makes them a potential target for future therapeutic approaches.

The Expression Level of HLA-E on Activated T Cells Determines Their Fate When Activated NK Cells Were Nearby Present.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1529-1529
Author(s):  
Sumiko Takao ◽  
Takayuki Ishikawa ◽  
Takashi Uchiyama
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Expression Level ◽  
T Cell Proliferation ◽  
Target Cells ◽  
Concanamycin A

Abstract Background: Recent studies demonstrated that natural killer (NK) cells play a regulatory role in immune responses. As for the interaction with T cells, NK cells coordinate T cell responses through not only influencing dendritic cell function, but also directly acting on T cells. Besides secreting several kinds of cytokines, NK cells also kill activated autologous T cells. However, whether NK cell-mediated cytotoxicity has any role in the primary T cell response remains elusive. Methods: Peripheral blood samples were obtained from healthy volunteers with written informed consent. Naïve CD25− CD4+ T cells, NK cells, and monocytes were isolated with magnetic beads. Monocyte-derived dendritic cells (MoDCs) were generated and either immature MoDCs (ImMoDCs) or LPS-stimulated MoDCs (LPS-MoDCs) were used. Naïve CD4+ T cells cultured with allogeneic MoDCs (allo-MoDCs) in the presence or absence of autologous NK cells pre-activated by IL-18 and IL-15. Naïve CD4+ T cells were labeled with PKH67 dye before culture and proliferation of CD4+T cells was detected by the dilution of PKH67 signals by flow cytometry. Results: We found that activated NK cells substantially inhibited CD4+ T cell proliferation in response to allo-MoDCs. The addition of cytokines such as IL-2 could not restore CD4+ T cell proliferation. However, NK cells were not able to inhibit CD4+ T cell growth when they were separated by a transmembrane. Even when naïve CD4+ T cells were cultured with LPS-MoDCs, which were resistant to NK-lysis, CD4+ T cell proliferation was also inhibited. Furthermore, even when activated NK cells were added to the culture after naïve CD4+ T cells were stimulated with allo-MoDCs for 24 hours, CD4+ T cell proliferation were also inhibited. These data suggested that NK cells directly acted on CD4+ T cells in this assay. Then we performed 4-hour cyototoxicity assays, in which activated (CD25+) CD4+ T cells isolated from the culture of naïve CD4+ T cells and allo-MoDCs at various time points were used as target cells and activated NK cells were used as effecter cells. Resting naïve CD4+ T cells were resistant to NK-lysis. However, at day 1, activated CD4+ T cells became susceptible. ImMoDC-stimulated CD4+ T cells were remarkably susceptible to NK-lysis, whereas LPS-DC-stimulated CD4+ T cells were relatively resistant. NK cells pretreated with concanamycin A could not lyse activated CD4+ T cells, indicating that killing was mediated by release of lytic granules. In contrast, at day 3, CD4+ T cells activated with either ImMoDCs or LPS-MoDCs were completely resistant to NK-lysis. We then analyzed the kinetics of MICA/B and HLA-E expression on naïve CD4+ T cells stimulated with allo-MoDCs. MICA/B expression, which was slightly induced at day 1 and peaked at day 3, was comparable between CD4+ T cells stimulated with ImMoDCs and those with LPS-MoDCs. Addition of blocking antibody against NKG2D to cytotoxic assays did not affect the susceptibility of activated CD4+ T cells to NK-lysis. In contrast, in agreement with the susceptibility to NK-lysis, HLA-E expression at day 1 was considerably higher on LPS-MoDC-stimulated CD4+ T cells than ImMoDC-stimulated CD4+ T cells. At day 3, HLA-E expression was further up-regulated, and similar expression levels were observed in both ImMoDC-stimulated CD4+ T cells and LPS-MoDC-stimulated CD4+ T cells. In addition, antibody-dependent blockade of the HLA-E-NKG2A interaction abrogated the relative resistance to NK-lysis of LPS-MoDC- stimulated CD4+ T cells at day 1. Conclusions and Discussion: Naïve CD4+ T cells became transiently susceptible to NK-lysis shortly after stimulated with allo-MoDCs, and, in our assay, NK-lysis of activated CD4+ T cells is the major mechanisms by which NK cells inhibited the proliferation of CD4+ T cells. High level of HLA-E expression on activated CD4+ T cells prevents NK-lysis. These data suggest that the expression level of HLA-E on activated CD4+ T cells determines their fate when activated NK cells are nearby present. HLA-E and NKG2A may become a new target of immunoregulation.

Two Novel WT-1 Derived Peptides Induce CD4+ peptide–specific T Cell Proliferation in Patients with Myelodysplastic Syndrome (MDS)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5432-5432
Author(s):  
Monica Bocchia ◽  
Micaela Ippoliti ◽  
Marzia Defina ◽  
Rosaria Crupi ◽  
Maristella Tassi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic Activity ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Wt1 Protein

Abstract The Wilms tumor gene WT1 is overexpressed in hematopoietic malignancies such as Myelodysplastic syndromes and leukemias and the WT1 protein was demonstrated to be an attractive target antigen for an immunotherapeutic approach to these diseases. Most of the efforts have been focused to the search for immunogenic peptides suitable for inducing cytotoxic T lymphocytes (CTLs) and to less extent for CD4+ T lymphocytes with potential cytotoxic activity. On this matter, in our previous experience with a p210-derived peptide vaccine developed for chronic myeloid leukemia patients with minimal residual disease, the main immune and therapeutic effect observed after vaccinations appeared to be mediated by peptide-specific CD4+ T cells induced by the longest peptide (25 mer) included in our vaccine. CML-peptide specific T cells were found to be either CD4+/perforin+ or CD4+/CD25+/Foxp3+ and we recently showed their direct cytotoxicity against a CML cell line. Thus to pursue a vaccine strategy mainly devoted to a similar CD4+ T cell immune response, we screened WT1 protein through Syfpeithi database to identify original peptides with a suitable length (23–25 amino acids) to be processed by several HLA class II molecules and to induce a strong CD4+ T cell stimulation. Additionally, in order to maximize the immunogenic potential of the novel peptides, we focused our attention on areas of the protein with known CTLs/CD4 T cells immunogenic epitopes. We identified two peptides that fulfilled these requirements: SEPQQMGSDVRDLNALLPAVPSLGG (WT1-iso5 64–88) which includes 5 amino acid from the alternative splicing derived isoform 5 of WT1 and the first 20 aa of “canonical” WT1 sequence and RPFMCAYPGCNKRYFKLSHLQMHSR (WT1321–345). Both 25mer peptides showed strong HLA binding properties for HLA-DRB1*0101, HLADRB1* 0401, HLA-DRB1*0701, HLA-DRB1*1101, HLA-DRB1*1501 and HLADRB1* 0301( DR17). We first tested them in vitro for their capability to induce peptide-specific CD4+ T cells. Briefly, CD4+ T cells freshly isolated from PBMC were cultured for 21 days in 5% AB human serum media while undergoing to 3 rounds of stimulation with autologous CD14+ cells and both WT1-iso5 64–88 and WT1 321–345 peptides at 20μg/ml in the presence of IL-15. This in vitro stimulation was performed in 3 normal subjects and in 3 MDS patients with high levels of bone marrow WT1 transcript (2 patients presenting a low-International Prognostic Scoring System (IPSS) refractory anemia (RA) and 1 with intermediate IPSS RA). In all 3 healthy donors tested, both peptides were able to induce peptide specific CD4+ T cell proliferation as measured by standard 3HThymidine assay, with a stimulation index (SI) ranging from 2.0 to 2.5 regardless of their HLA-DR phenotype ( SI= cpm CD4+ T cells plus test peptides/CD4+ T cell alone or CD4+ T cells plus control peptides; peptide-specific T cell proliferation was considered positive for SI≥2). Similar results were obtained in all 3 MDS patients in which WT1-iso5 64–88 and WT1 321–345 induced peptide-specific CD4+ T cell proliferation with a SI value of 2.5, 2.9 and 3.0 respectively. In conclusion the present study identified 2 novel WT1-derived 25 mer peptides which were able to easily induce in vitro a peptide-specific CD4+ T cell response in MDS patients. WT1-specific CD4+ T cells proliferated with similar SI values in normal donors and in WT1 positive MDS patients, the latter being highly exposed to this antigen and thus potentially tolerant to it. A possible cytotoxic activity of these WT1-specific CD4+ T cells is under evaluation and in vivo vaccinations of low-intermediate IPSS MDS patients with these peptides are planned.

scholarly journals Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4168-4174 ◽  
Author(s):  
Xiaolei Wang ◽  
Huanbin Xu ◽  
Bapi Pahar ◽  
Xavier Alvarez ◽  
Linda C. Green ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus

Abstract Infants infected with HIV have a more severe course of disease and persistently higher viral loads than HIV-infected adults. However, the underlying pathogenesis of this exacerbation remains obscure. Here we compared the rate of CD4+ and CD8+ T-cell proliferation in intestinal and systemic lymphoid tissues of neonatal and adult rhesus macaques, and of normal and age-matched simian immunodeficiency virus (SIV)–infected neonates. The results demonstrate infant primates have much greater rates of CD4+ T-cell proliferation than adult macaques, and that these proliferating, recently “activated” CD4+ T cells are infected in intestinal and other lymphoid tissues of neonates, resulting in selective depletion of proliferating CD4+ T cells in acute infection. This depletion is accompanied by a marked increase in CD8+ T-cell activation and production, particularly in the intestinal tract. The data indicate intestinal CD4+ T cells of infant primates have a markedly accelerated rate of proliferation and maturation resulting in more rapid and sustained production of optimal target cells (activated memory CD4+ T cells), which may explain the sustained “peak” viremia characteristic of pediatric HIV infection. Eventual failure of CD4+ T-cell turnover in intestinal tissues may indicate a poorer prognosis for HIV-infected infants.

scholarly journals Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type.

1995 ◽  
Vol 181 (3) ◽  
pp. 1081-1089 ◽  
Author(s):  
H Secrist ◽  
R H DeKruyff ◽  
D T Umetsu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
T Cell Proliferation ◽  
High Concentrations ◽  
Antigen Presenting

We have previously shown that CD4+ T cells from allergic individuals are predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced IL-4 production in an allergen-specific fashion. The mechanism that results in the reduction of IL-4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells. In this report, we demonstrated that CD4+ T cells from allergic donors produced high levels of IL-4 when stimulated with low concentrations of allergen (0.003-0.01 micrograms/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the same responding CD4+ T cell population produced little IL-4 when stimulated with high concentrations of allergen (10-30 micrograms/ml), especially when monocytes were used as antigen-presenting cells (APC). The quantity of IL-4 produced was also found to be inversely related to the extent of proliferation of the CD4+ T cells in response to allergen/antigen; maximal proliferation of CD4+ T cells occurred in response to high concentrations of antigen when IL-4 production was minimal. Antigen presentation by B cell-enriched populations, instead of monocytes, induced less CD4+ T cell proliferation, but induced much greater IL-4 synthesis. Moreover, the addition of increasing numbers of APC (either B cells or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased IL-4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the proliferative signal to T cells, greatly affect the quantity of IL-4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and APC type suggest that methods that preferentially enhance allergen uptake by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disease.

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