Loss of IL-7Rα is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients

Réthi, Bence; Fluur, Caroline; Atlas, Ann; Krzyżowska, Małgorzata; Mowafi, Frida; Grützmeier, Sven; Milito, Angelo De; Bellocco, Rino; Falk, Kerstin I.; Rajnavölgyi, Éva; Chiodi, Francesca

doi:10.1097/01.aids.0000189848.75699.0f

Cited by 121 publications

(124 citation statements)

References 45 publications

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“…4, i and j, respectively). Measurement of the IL-7R␣ expression allowed us to discriminate CD45RA ϩ naive and effector T cells as we previously showed a massive down-regulation of IL-7R␣ on the CD45RA ϩ CCR7 Ϫ effectors both in HIV-infected and noninfected individuals (43). Our results showed that the increased serum IL-7 levels were associated with the increasing Fas expression on the IL-7R␣ ϩ naive and memory subsets.…”

Section: Figure 3 Il-7 Treatment Increases Fas Expression Of T Cellssupporting

confidence: 67%

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Fluur

Milito

Fry

et al. 2007

The Journal of Immunology

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IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

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Section: Figure 3 Il-7 Treatment Increases Fas Expression Of T Cellssupporting

confidence: 67%

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Fluur

Milito

Fry

et al. 2007

The Journal of Immunology

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“…For example, although Bcl-2 was found to be expressed in peripheral T-lymphocytes and strongly correlated with spontaneous T cell apoptosis [32][33][34][35], in lymph nodes, Bcl-2 was detected primarily in the B (mantle zone of the germinal centers) and not in the T cell area. Similarly, IL-7Ra was found to be expressed on peripheral T and B cells, and peripheral CD4+ T cell depletion correlated well with the down-regulation of IL-7Ra [36,37]. In lymph nodes, IL-7Ra which increased after therapy was detectable only in the germinal centers and not in the T cell area.…”

Section: Discussionmentioning

confidence: 83%

“…In lymph nodes, IL-7Ra which increased after therapy was detectable only in the germinal centers and not in the T cell area. The absence of IL-7Ra expression in the T cell area resembles those peripheral T cells in which a strong association of decreased IL-7Ra expression with low Bcl-2 expression has been found [36,37]. In lymph nodes, a significant down-regulation of TRAIL was found after therapy due primarily to the reduction of cells of the phagocytic type, whereas TRAIL was not identifiable in B or T lymphocytes.…”

Section: Discussionmentioning

confidence: 84%

Effect of Antiretroviral Therapy on Apoptosis Markers and Morphology in Peripheral Lymph Nodes of HIV-Infected Individuals

et al. 2008

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Background: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. Patients and Methods: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes.

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“…11 In HIVinfected patients, although IL-7 levels are elevated, the expression of IL-7Ra on T-cells and signalling through the receptor (measured by STAT-5 phosphorylation) is impaired and only partially corrected with cART. 12,13 Previous studies have found that impaired IL-7 responsiveness is significantly associated with poor CD4 T-cell recovery following cART. 14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression).…”

Section: Introductionmentioning

confidence: 99%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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Loss of IL-7Rα is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients

Cited by 121 publications

References 45 publications

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Effect of Antiretroviral Therapy on Apoptosis Markers and Morphology in Peripheral Lymph Nodes of HIV-Infected Individuals

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

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