HIV Controllers Exhibit Effective CD8+ T Cell Recognition of HIV-1-Infected Non-activated CD4+ T Cells

Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen “indirectly,” as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are “unlinked” on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the “semidirect” pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell–mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation.

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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 ◽

10.1182/blood.v96.1.195.013k51_195_202 ◽

2000 ◽

Vol 96 (1) ◽

pp. 195-202 ◽

Cited By ~ 1

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.

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Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Journal of Virology ◽

10.1128/jvi.00719-19 ◽

2019 ◽

Vol 93 (20) ◽

Cited By ~ 2

Author(s):

Thomas van Stigt Thans ◽

Janet I. Akko ◽

Annika Niehrs ◽

Wilfredo F. Garcia-Beltran ◽

Laura Richert ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Line ◽

Nk Cell ◽

Cytoplasmic Tail ◽

Cytotoxic T Cell ◽

Cell Recognition ◽

T Cell Recognition ◽

Infected Cells ◽

Hiv 1

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surfaces of infected cells. Recent evidence identified HLA-E, a nonclassical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8+T-cell and natural killer (NK) cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4+T cells with primary HIV-1 strains and observed that a subset downregulated HLA-E. Two primary strains of HIV-1 that induced the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in a T-cell line, as well as tail swap experiments exchanging the cytoplasmic tail of HLA-A2 with that of HLA-E, demonstrated that Nef modulated HLA-E surface levels and targeted the cytoplasmic tail of HLA-E. Furthermore, infection of primary CD4+T cells with HIV-1 mutants showed that a lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, the results of this study demonstrate for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4+T cells, potentially rendering them less vulnerable to CD8+T-cell recognition but at increased risk of NKG2A+NK cell killing.IMPORTANCEFor almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic-T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that HIV-1 infection thereby maintained inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell line-adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as an important modulator of CD8+T-cell and NKG2A+NK cell functions, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.

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Susceptibility to CD8 T-Cell–Mediated Killing Influences the Reservoir of Latently HIV-1–Infected CD4 T Cells

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e3182a1bc81 ◽

2014 ◽

Vol 65 (1) ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Maria J. Buzon ◽

Yue Yang ◽

Zhengyu Ouyang ◽

Hong Sun ◽

Katherine Seiss ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Hiv 1

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Characteristics of Plasmacytoid Dendritic Cell and CD4+ T Cell in HIV Elite Controllers

Clinical and Developmental Immunology ◽

10.1155/2012/869505 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Jean-Philippe Herbeuval ◽

Nikaïa Smith ◽

Jacques Thèze

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cd4 T Cells ◽

Plasmacytoid Dendritic Cell ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Hiv Controllers ◽

Hiv 1

Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load and massive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers), and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers.

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FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection

Journal of Leukocyte Biology ◽

10.1189/jlb.0507281 ◽

2007 ◽

Vol 83 (2) ◽

pp. 254-262 ◽

Cited By ~ 64

Author(s):

Lishomwa C. Ndhlovu ◽

Christopher P. Loo ◽

Gerald Spotts ◽

Douglas F. Nixon ◽

Frederick M. Hecht

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd8 T Cell ◽

Hiv 1

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Degenerate specificity of HTLV-1–specific CD8+ T cells during viral replication in patients with HTLV-1–associated myelopathy (HAM/TSP)

Blood ◽

10.1182/blood-2002-08-2477 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3074-3081 ◽

Cited By ~ 19

Author(s):

Ryuji Kubota ◽

Yoshitaka Furukawa ◽

Shuji Izumo ◽

Koichiro Usuku ◽

Mitsuhiro Osame

Keyword(s):

T Cells ◽

T Cell ◽

Viral Replication ◽

Cd8 T Cells ◽

Proviral Load ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Recognition ◽

T Cell Recognition ◽

Cell Responses

AbstractHuman T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1 infection, in which HTLV-1–infected CD4+ T cells and HTLV-1–specific CD8+ T cells may play a role in the disease pathogenesis. Patients with HAM/TSP have high proviral loads despite vigorous virus-specific CD8+ T-cell responses; however, it is unknown whether the T cells are efficient in eliminating the virus in vivo. To define the dynamics of HTLV-1–specific CD8+T-cell responses, we investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes in an immunodominant viral epitope, frequency of HTLV-1–specific T cells, and degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the frequency and the degeneracy of the HTLV-1–specific CD8+ T cells correlated well with proviral load in the longitudinal study. The proviral load was much higher in a patient with low degeneracy of HTLV-1–specific T cells compared to that in a patient with comparable frequency but higher degeneracy of the T cells. Furthermore, in a larger number of patients divided into 2 groups by the proviral load, those with high proviral load had lower degeneracy of T-cell recognition than those with low proviral load. Sequencing analysis revealed that epitope mutations were remarkably increased in a patient when the frequency and the degeneracy were at the lowest. These data suggest that HTLV-1–specific CD8+ T cells with degenerate specificity are increased during viral replication and control the viral infection.

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Reliable Estimation of CD8 T Cell Inhibition of In Vitro HIV-1 Replication

Frontiers in Immunology ◽

10.3389/fimmu.2021.666991 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yinyan Xu ◽

Ann Marie Weideman ◽

Maria Abad-Fernandez ◽

Katie R. Mollan ◽

Sallay Kallon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

People Living With Hiv ◽

Viral Inhibition ◽

Hiv Replication ◽

Virus Inhibition ◽

Hiv 1

The HIV-1 viral inhibition assay (VIA) measures CD8 T cell-mediated inhibition of HIV replication in CD4 T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. The VIA has multiple sources of variability arising from in vitro HIV infection and co-culture of two T cell populations. Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence interval. An Excel template is provided to facilitate calculations. Virus inhibition was higher in people living with HIV suppressed on antiretroviral therapy (n=14, mean: 40.0%, median: 43.8%, range: 8.2 to 73.3%; p < 0.0001, two-tailed, exact Mann-Whitney test) compared to HIV-seronegative donors (n = 21, mean: -13.7%, median: -14.4%, range: -49.9 to 20.9%) and was stable over time (n = 6, mean %COV 9.4%, range 0.9 to 17.3%). Cross-sectional data were used to define 8% inhibition as the threshold to confidently detect specific CD8 T cell activity and determine the minimum number of culture replicates and p24+ cells needed to have 90% statistical power to detect this threshold. Last, we note that, in HIV seronegative donors, the addition of CD8 T cells to HIV infected CD4 T cells consistently increased HIV replication, though the level of increase varied markedly between donors. This co-culture effect may contribute to the weak correlations observed between CD8 T cell VIA and other measures of HIV-specific CD8 T cell function.

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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 ◽

10.1182/blood.v96.1.195 ◽

2000 ◽

Vol 96 (1) ◽

pp. 195-202 ◽

Cited By ~ 47

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

Abstract 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.

Download Full-text