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

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 (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 α₄β₇⁺ gut-homing T_EM (α₄β₇⁺ T_EM), we found that α₄β₇⁺ 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 α₄β₇⁺ T_EM stimulated with TGF-β1 (TGF-β). The T_CM properties of the TGF-β-induced T_EM-derived T_CM (α₄β₇⁺ 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 α₄β₇⁺ T_CM could differentiate from α₄β₇⁺ 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.