Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1660-1667 ◽  
Author(s):  
John J. Zaunders ◽  
Mee Ling Munier ◽  
Daniel E. Kaufmann ◽  
Susanna Ip ◽  
Pat Grey ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
Fold Increase ◽  
Primary Response ◽  
T Helper 1 ◽  
Ki 67 ◽  
Effector Cells ◽  
Hiv 1

Abstract We investigated whether HIV-1 antigen-specific CD4+ T cells expressed the viral coreceptor CCR5 during primary HIV-1 infection (PHI). In the peripheral blood of subjects with very early PHI (< 22 days after onset of symptoms), there was a 10- to 20-fold increase in the proportion of highly activated (CD38+++) and proliferating (Ki-67+) CD4+ T cells that expressed CCR5+, and were mostly T-cell intracellular antigen-1 (TIA-1)+ perforin+ granzyme B+. Inthe same patient samples, CD4+ T cells producing interferon (IFN)–γ in response to HIV group-specific antigen (Gag) peptides were readily detected (median, 0.58%) by intracellular cytokine assay—these cells were again predominantly CD38+++, Ki-67+, and TIA-++, as well as Bcl-2low. On average, 20% of the Gag-specific CD4+ T cells also expressed interleukin-2 (IL-2) and were CD127 (IL-7R)+. Taken together, these results suggest that Gag-specific T-helper 1 (Th1) effector cells express CCR5 during the primary response and may include precursors of long-term self-renewing memory cells. However, in PHI subjects with later presentation, antigen-specific CD4+ T cells could not be readily detected (median, 0.08%), coinciding with a 5-fold lower level of the CCR5+CD38+++ CD4+ T cells. These results suggest that the antiviral response to HIV-1 infection includes highly activated CCR5+CD4+ cytotoxic effector cells, which are susceptible to both apoptosis and cytopathic infection with HIV-1, and rapidly decline.

scholarly journals CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

2021 ◽  
Vol 22 (2) ◽  
pp. 912
Author(s):  
Nabila Seddiki ◽  
John Zaunders ◽  
Chan Phetsouphanh ◽  
Vedran Brezar ◽  
Yin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Significant Proportion ◽  
Long Term Memory ◽  
Ki 67 ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

scholarly journals Preexisting memory CD4+ T cells contribute to the primary response in an HIV-1 vaccine trial

2021 ◽  
Vol 131 (23) ◽  
Author(s):  
Suzanne L. Campion ◽  
Elena Brenna ◽  
Elaine Thomson ◽  
Will Fischer ◽  
Kristin Ladell ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Vaccine Trial ◽  
Primary Response ◽  
Memory Cd4 T Cells ◽  
Hiv 1

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

scholarly journals Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

1994 ◽  
Vol 179 (2) ◽  
pp. 447-456 ◽  
Author(s):  
S L Reiner ◽  
S Zheng ◽  
Z E Wang ◽  
L Stowring ◽  
R M Locksley
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Interleukin 12 ◽  
Insect Vector ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
Effector Cells

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.

scholarly journals Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7967-7979 ◽  
Author(s):  
Xavier Dagenais-Lussier ◽  
Mouna Aounallah ◽  
Vikram Mehraj ◽  
Mohamed El-Far ◽  
Cecile Tremblay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
Tryptophan Catabolism ◽  
T Cell Survival ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTEarly HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidantN-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection.IMPORTANCEThe persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.

Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy

10.1038/9498 ◽  
1999 ◽  
Vol 5 (6) ◽  
pp. 651-655 ◽  
Author(s):  
Tae-Wook Chun ◽  
Delphine Engel ◽  
Stephanie B. Mizell ◽  
Claire W. Hallahan ◽  
Maria Fischette ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Highly Active ◽  
Latently Infected ◽  
Hiv 1

Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1–infected subjects with progressive disease: changes after antiretroviral therapy

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 966-972 ◽  
Author(s):  
Alexandre Harari ◽  
Stéphanie Petitpierre ◽  
Florence Vallelian ◽  
Giuseppe Pantaleo
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Progressive Disease ◽  
Early Stage ◽  
Interleukin 2 ◽  
Previous History ◽  
Partial Recovery ◽  
Ifn Γ ◽  
Hiv 1

AbstractHIV-1- and cytomegalovirus (CMV)-specific CD4 T-cell-mediated antiviral immunity was evaluated by assessing the frequency of interleukin 2 (IL-2)- and interferon γ (IFN-γ)-secreting cells following antigen-specific stimulation in blood and lymph node. HIV-1-infected subjects with progressive disease at early stage of infection with no previous history of antiretroviral therapy (ART), subjects with nonprogressive disease, and HIV-negative subjects were studied. On the basis of the ability to secrete IL-2 and IFN-γ, 3 functionally distinct populations of CD4 T cells were identified: (1) IL-2-secreting cells; (2) IL-2/IFN-γ-secreting cells; and (3) IFN-γ-secreting cells. CMV-specific CD4 T cells were almost equally distributed within the 3 functionally distinct cell populations in the 3 study groups as well as HIV-1-specific CD4 T cells in subjects with nonprogressive disease. However, a skewing toward IFN-γ-secreting cells (70% of HIV-1-specific CD4 T cells) was observed in subjects with progressive disease, and IL-2- and IL-2/IFN-γ-secreting cells were almost absent. The frequencies of IL-2- and of IL-2/IFN-γ-secreting HIV-1-specific CD4 T cells were negatively correlated with the levels of viremia. Interestingly, prolonged ART was able to correct the skewed representation of different populations of HIV-1-specific CD4 T cells but was associated with only a partial recovery of IL-2-secreting cells. These results indicate that the composition of the pool of functionally distinct virus-specific CD4 T cells is important for virus control. (Blood. 2004;103:966-972)

Interleukin-2-Producing CD4+OX40+ T Cell as a Target for the Treatment of Chronic Graft-Versus-Host-Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1816-1816
Author(s):  
Takero Shindo ◽  
Takayuki Ishikawa ◽  
Akiko Fukunaga ◽  
Toshiyuki Hori ◽  
Takashi Uchiyama
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
Host Disease ◽  
Effector Cells ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract Chronic graft-versus-host-disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious complication, for which limited therapeutic approaches exist. Thymus-derived autoreactive as well as alloreactive T cells are shown to be involved in the development of chronic GVHD and CD4+ T cells are regarded to play a central role. OX40 (CD134) is known to play an important role in co-stimulation and survival elongation of CD4+ T cells, and murine models revealed that the interaction of OX40/OX40-ligand constitutes an essential parts in autoimmune and alloimmune responses. Since we showed that the increase of CD4+OX40+ T cells in peripheral blood of allo-HSCT recipients precedes the occurrence of chronic GVHD (Kotani A et al. Blood2001; 98: 3162–4), we have paid attention to the role of peripheral blood CD4+OX40+ T cells in the development of chronic GVHD. To further know the characteristics of peripheral blood CD4+OX40+ T cells from patients after allo-HSCT, we analyzed surface phenotype and the ability of cytokine production of CD4+ T cells from 25 allo-HSCT recipients. A majority of CD4+OX40+ T cells showed CD45RO+CD62L+CCR7+, while CD4+OX40− T cells were mainly CD45RO+CD62L−CCR7−. When stimulated with PMA and ionomycin, a significant part of CD4+OX40+ T cells produced interleukin-2 (IL-2). In contrast, a majority of CD4+OX40−HLA-DR+ T cells, the ratio of which also increased in peripheral blood of allo-HSCT recipients, produced interferon-γ (IFN-γ). Thus, the pattern of the expression of activation antigens on CD4+ T cells is a landmark of the potential to produce IL-2 or IFN-γ. When clinical data were combined, patients suffering from chronic GVHD showed increased ratio of IL-2-producing CD4+OX40+ T cells among CD4+ T cells (more than 10%). In fact, it correlates more closely (p=0.016) to the occurrence of chronic GVHD than the ratio of CD4+OX40+ T cells or that of IL-2-producing CD4+ T cells (p=0.06). Interestingly, the ratio of IFN-γ-producing CD4+ T cells does not correlate (p=0.95), suggesting that they do not contribute to the process of ongoing chronic GVHD. As CD4+OX40+ T cells share the characteristics of central memory T cells, we hypothesized that CD4+OX40+ T cells, which home secondary lymphoid organs, are stimulated with antigens and develop into effector cells, some of which induce chronic GVHD. Then we collected CD4+ T cells from recipients of allo-HSCT and sorted them into OX40+ and OX40− fractions. When sorted cells were stimulated with immobilized anti-CD3 and soluble anti-CD28 (CD3/28 stimulation), IL-2-producing cells were detected mainly in OX40+ fraction and IFN-γ-producing cells were abundantly and exclusively observed in OX40− fraction. When sorted cells were stimulated with CD3/28 for 48 hr, followed by 4-day cultivation with IL-2, OX40+ cells showed vigorous growth without reducing viability. In addition, re-stimulation with CD3/CD28 revealed that OX40+ cells produce a large amount of IFN-γ or IL-4. In this way, peripheral blood CD4+OX40+ T cells have potential to easily differenciate into effector cells, which may contribute to the development of chronic GVHD. The signaling from OX40 may also accelerate this process. Targeted therapy against IL2-producing CD4+OX40+ T cells may afford a breakthrough in the treatment of chronic GVHD.

Interleukin-2 therapy and CD4+ T cells in HIV-1 infection

The Lancet ◽  
2006 ◽  
Vol 367 (9505) ◽  
pp. 93-95 ◽  
Author(s):  
Sandro Vento ◽  
Francesca Cainelli ◽  
Zelalem Temesgen
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Hiv 1
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