ABSTRACT
HIV-1 transmission occurs mainly through mucosal tissues. During mucosal transmission, HIV-1 preferentially infects α
4
β
7
+
gut-homing CCR7
−
CD4
+
effector/effector memory T cells (T
EM
) and results in massive depletion of these cells and other subsets of T
EM
in gut-associated lymphoid tissues. However, besides being eliminated by HIV-1, the role of T
EM
during the early stage of infection remains inconclusive. Here, using
in vitro
-induced α
4
β
7
+
gut-homing T
EM
(α
4
β
7
+
T
EM
), we found that α
4
β
7
+
T
EM
differentiated into CCR7
+
CD4
+
central memory T cells (T
CM
). This differentiation was HIV-1 independent but was inhibited by SB431542, a specific transforming growth factor β (TGF-β) receptor I kinase inhibitor. Consistently, T
EM
-to-T
CM
differentiation was observed in α
4
β
7
+
T
EM
stimulated with TGF-β1 (TGF-β). The T
CM
properties of the TGF-β-induced T
EM
-derived T
CM
(α
4
β
7
+
T
CM
) 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 T
CM
differentiation also held in T
EM
directly isolated from peripheral blood. To investigate the significance of the TGF-β-dependent T
EM
-to-T
CM
differentiation in HIV/AIDS pathogenesis, we observed that both productively and latently infected α
4
β
7
+
T
CM
could differentiate from α
4
β
7
+
T
EM
in the presence of TGF-β during HIV-1 infection. Collectively, this study not only provides a new insight for the plasticity of T
EM
but also suggests that the TGF-β-dependent T
EM
-to-T
CM
differentiation is a previously unrecognized mechanism for the formation of latently infected T
CM
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 (T
EM
), 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 T
EM
after infection. Our findings suggest previously unrecognized roles of CD4 T
EM
in HIV-1 pathogenesis.
Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro