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α4β7+ CD4+ Effector/Effector Memory T Cells Differentiate into Productively and Latently Infected Central Memory T Cells by Transforming Growth Factor β1 during HIV-1 Infection.

Abstract：

:HIV-1 transmission occurs mainly through mucosal tissues. During mucosal transmission, HIV-1 preferentially infects α4β7+ gut-homing CCR7- CD4+ effector/effector memory T cells (TEM) and results in massive depletion of these cells and other subsets of TEM in gut-associated lymphoid tissues. However, besides being eliminated by HIV-1, the role of TEM during the early stage of infection remains inconclusive. Here, using in vitro-induced α4β7+ gut-homing TEM (α4β7+ TEM), we found that α4β7+ TEM differentiated into CCR7+ CD4+ central memory T cells (TCM). This differentiation was HIV-1 independent but was inhibited by SB431542, a specific transforming growth factor β (TGF-β) receptor I kinase inhibitor. Consistently, TEM-to-TCM differentiation was observed in α4β7+ TEM stimulated with TGF-β1 (TGF-β). The TCM properties of the TGF-β-induced TEM-derived TCM (α4β7+ TCM) were confirmed by their enhanced CCL19 chemotaxis and the downregulation of surface CCR7 upon T cell activation in vitro Importantly, the effect of TGF-β on TCM differentiation also held in TEM directly isolated from peripheral blood. To investigate the significance of the TGF-β-dependent TEM-to-TCM differentiation in HIV/AIDS pathogenesis, we observed that both productively and latently infected α4β7+ TCM could differentiate from α4β7+ TEM in the presence of TGF-β during HIV-1 infection. Collectively, this study not only provides a new insight for the plasticity of TEM but also suggests that the TGF-β-dependent TEM-to-TCM differentiation is a previously unrecognized mechanism for the formation of latently infected TCM after HIV-1 infection.IMPORTANCE HIV-1 is the causative agent of HIV/AIDS, which has led to millions of deaths in the past 30 years. Although the implementation of highly active antiretroviral therapy has remarkably reduced the HIV-1-related morbidity and mortality, HIV-1 is not eradicated in treated patients due to the presence of latent reservoirs. Besides, the pathogenesis in CD4 T cells early after infection still remains elusive. Immediately after HIV-1 mucosal infection, CD4 T cells are preferentially infected and depleted. However, in addition to being depleted, the other roles of the CD4 T cells, especially the effector/effector memory T cells (TEM), in disease progression are not completely understood. The significance of this study is in revealing a novel mechanism for the formation of latently HIV-1-infected central memory CD4 T cells, a major latent reservoir from CD4 TEM after infection. Our findings suggest previously unrecognized roles of CD4 TEM in HIV-1 pathogenesis.

journal_name

J Virol

journal_title

Journal of virology

authors

Cheung KW,Wu T,Ho SF,Wong YC,Liu L,Wang H,Chen Z

doi

10.1128/JVI.01510-17

subject

Has Abstract

pub_date

2018-03-28 00:00:00

issue

eissn

0022-538X

issn

1098-5514

pii

JVI.01510-17

journal_volume

pub_type

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α4β7+ CD4+ Effector/Effector Memory T Cells Differentiate into Productively and Latently Infected Central Memory T Cells by Transforming Growth Factor β1 during HIV-1 Infection.