Perforin-low memory CD8<sup>+</sup>cells are the predominant T cells in normal humans that synthesize the β-chemokine macrophage inflammatory protein-1β

Kamin-Lewis, Roberta; Abdelwahab, Sayed F.; Trang, Christine; Baker, Amanda; DeVico, Anthony L.; Gallo, Robert C.; Lewis, George K.

doi:10.1073/pnas.161298998

Cited by 26 publications

(19 citation statements)

References 48 publications

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“…We found MIP-1β detection in breast milk was associated with lower risk of infant HIV transmissions between delivery and 1 month postpartum, independent of breast milk viral load and breast milk IFN-γ responses. A large proportion of activated CD8 + T cells secrete both IFN-γ and MIP-1β [29,32], consistent with the correlation observed in our study between breast milk IFN-γ responses and MIP-1β levels. MIP-1β could protect against HIV entry by binding to CCR5 on target cells in either the breast milk and/or the infant gut.…”

Section: Discussionsupporting

confidence: 89%

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Lohman-Payne¹,

Slyker²,

Moore³

et al. 2012

Aids

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Objective Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection. Design A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age. Methods In a Kenyan cohort of HIV-infected mothers, blood and breastmilk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age. Results IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-γ response (P =0.08, P =0.04, respectively), breast milk MIP-1β detection (P =0.05), and plasma (P =0.004) and breast milk (P =0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1β, breast milk IFN-γ responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092–0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44–0.97). Conclusion These data show breast milk HIV-gag-specific IFN-γ cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses.

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Section: Discussionsupporting

confidence: 89%

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Lohman-Payne¹,

Slyker²,

Moore³

et al. 2012

Aids

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“…Our data showing accelerated influx of cells expressing granzymes A and B in recipients of MIP-1␣ Ϫ/Ϫ cells concomitant with decreased MIP-1␤ production are consistent with recent data that demonstrate an inverse relationship of MIP-1␤ production and cytolytic T cells in humans. 29 The decrease in systemic IL-13 levels in MIP-1␣ Ϫ/Ϫ spleen cell recipients indicates a skewing away from an anti-inflammatory, 30 or Th2-type, milieu in these mice. This may be a contributing factor to the accelerated IPS in these recipients, since Th2 cells usually have a lesser capacity to induce lethal GVHD manifestations.…”

Section: Discussionmentioning

confidence: 96%

Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1α (CCL3) after allogeneic BMT in mice

Panoskaltsis‐Mortari

Hermanson

Taras

et al. 2003

Blood

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Idiopathic pneumonia syndrome (IPS) is a significant cause of morbidity and mortality after bone marrow transplantation (BMT) in humans. We developed a murine IPS model in which lethal pre-BMT conditioning and allogeneic T cells results in the recruitment of host monocytes and then donor T cells into the lung by day 7 after BMT, concomitant with development of severe lung dysfunction. We reported the T cell-dependent production of the T cell-attracting chemokine macrophage inflammatory protein-1␣ (MIP-1␣) in the lungs of such recipient mice. We reasoned that MIP-1␣ might be a critical mediator of IPS.

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“…By example, HIV-specific CD8 ϩ T cells have been reported to express only low levels of perforin, a key mediator of cytolytic activity, even though they can still produce antiviral cytokines and chemokines (21)(22)(23). Defective cytolytic activity has been associated with a specific CD8 ϩ T cell subpopulation, the less differentiated CD8…”

Section: T Cells Are Critical For Effective Cd8mentioning

confidence: 99%

HIV-Induced Changes in T Cell Signaling Pathways

Schweneker¹,

Favre²,

Martin

et al. 2008

The Journal of Immunology

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Infection with HIV usually results in chronic activation of the immune system, with profound quantitative and qualitative changes in the T cell compartment. To better understand the mechanistic basis for T cell dysfunction and to discern whether such mechanisms are reversed after effective antiviral treatment, we analyzed changes in signaling pathways of human CD4+ and CD8+ T cells from 57 HIV-infected subjects in varying stages of disease progression and treatment, including long-term nonprogressors, progressors, and chronically infected subjects provided effective antiretroviral therapy (responders). A previously described PhosFlow method was adapted and optimized so that protein phosphorylation could be visualized in phenotypically defined subpopulations of CD4+ and CD8+ T cells (naive, memory, and effector) by flow cytometry. T cell signaling induced by TCR cross-linking, IL-2, or PMA/ionomycin was found to be blunted within all T cell subpopulations in those with progressive HIV disease compared with long-term nonprogressors and responders. Although alterations in cellular signaling correlated with levels of basal phosphorylation, viral load, and/or expression of programmed death-1, it was the level of basal phosphorylation that appeared to be the factor most dominantly associated with impaired signaling. Notably, provision of effective antiretroviral therapy was associated with a normalization of both basal phosphorylation levels and T cell signaling. These data, in aggregate, suggest that generalized dysfunction of the T cell compartment during progressive HIV disease may be in part dependent upon an increased basal level of phosphorylation, which itself may be due to the heightened state of immune activation found in advanced disease.

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Perforin-low memory CD8⁺cells are the predominant T cells in normal humans that synthesize the β-chemokine macrophage inflammatory protein-1β

Cited by 26 publications

References 48 publications

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1α (CCL3) after allogeneic BMT in mice

HIV-Induced Changes in T Cell Signaling Pathways

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Perforin-low memory CD8+cells are the predominant T cells in normal humans that synthesize the β-chemokine macrophage inflammatory protein-1β

Cited by 26 publications

References 48 publications

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission

Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1α (CCL3) after allogeneic BMT in mice

HIV-Induced Changes in T Cell Signaling Pathways

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Perforin-low memory CD8⁺cells are the predominant T cells in normal humans that synthesize the β-chemokine macrophage inflammatory protein-1β