CD4 T cell contact drives macrophage cell cycle progression and susceptibility to lentiviral transduction

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Abstract Macrophages are typically quiescent cells residing in G0, though tissue macrophages have been shown to proliferate locally in tissues; we previously demonstrated that differentiated monocyte derived macrophages (MDM) can be stimulated to re-enter G1 phase of the cell cycle from G0, without cell division. Entry into G1 correlates with an increase in CDK1 expression which phosphorylates the deoxynucleotide-triphosphate hydrolase SAMHD1 at position 592. SAMHD1 not only regulates cellular dNTP levels, but is also a restriction factor for virus replication of HIV-1 and DNA viruses. Here we show that contact with autologous CD4 T cells leads to antigen-independent macrophage cell cycle progression from G0-G1, accompanied by expression of cell cycle associated proteins, including CDK1, and the activation of the canonical MEK-ERK pathway. Further, macrophage cell cycle progression can be blocked not only by anti-cancer drugs targeting the MEK-ERK axis such as Palcociclib, but also by pre-treatment with EGFR antibody, providing additional evidence for cell surface interactions driving proliferative responses. Cell contact with uninfected CD4 T cells renders macrophages ten-fold more susceptible to transduction with VSV-G pseudotyped HIV-1 particles.

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