Expression and regulation of Schlafen (SLFN) family members in primary human monocytes, monocyte-derived dendritic cells and T cells

Schlafen (SLFN/Slfn) family members have been investigated for their involvement in fundamental cellular processes including growth regulation, differentiation and control of viral replication. However, most research has been focused on the characterization of Slfns within the murine system or in human cell lines. Since little is known about SLFNs in primary human immune cells, we set out to analyze the expression and regulation of the six human SLFN genes in monocytes, monocyte-derived dendritic cells (moDCs) and T cells. Comparison of SLFN gene expression across these three cell types showed high mRNA expression of SLFN11 in monocytes and moDCs and high SLFN5 expression in T cells, indicating functional importance within these cell types. Differentiation of monocytes to moDCs leads to the gradual upregulation of SLFN12L and SLFN13 while SLFN12 levels were decreased by differentiation stimuli. Stimulation of moDCs via human rhinovirus, lipopolysaccharide, or IFN-α lead to strong upregulation of SLFN gene expression, while peptidoglycan poorly stimulated regulation of both SLFNs and the classical interferon-stimulated gene MxA. T cell activation was found to downregulate the expression of SLFN5, SLFN12 and SLFN12L, which was reversible upon addition of exogenous IFN-α. In conclusion, we demonstrate, that SLFN gene upregulation is mainly dependent on autocrine type I interferon signaling in primary human immune cells. Rapid decrease of SLFN expression levels following T cell receptor stimulation indicates a role of SLFNs in the regulation of human T cell quiescence

Immunology / Engagement of distinct epitopes on CD43 induces different co-stimulatory pathways in human T cells

Co-receptors, being either co-stimulatory or co-inhibitory, play a pivotal role in T-cell immunity. Several studies have indicated that CD43, one of the abundant T-cell surface glycoproteins, acts not only as a potent co-receptor but also as a negative regulator for T-cell activation. Here we demonstrate that co-stimulation of human peripheral blood (PB) T cells through two distinct CD43 epitopes recognized by monoclonal antibodies (mAb) CD43-6E5 (T6E5-act) and CD43-10G7 (T10G7-act) potently induced T-cell proliferation. However, T-cell co-stimulation through two CD43 epitopes differentially regulated activation of nuclear factor of activated T cells (NFAT) and nuclear factor-kappa B (NF-kappa B) transcription factors, T-cell cytokine production and effector function. T6E5-act produced high levels of interleukin-22 (IL-22) and interferon-gamma (IFN-gamma) similar to T cells activated via CD28 (TCD28-act), whereas T10G7-act produced low levels of inflammatory cytokines but higher levels of regulatory cytokines transforming growth factor-beta (TGF-beta) and interleukin-35 (IL-35). Compared with T6E5-act or to TCD28-act, T10G7-act performed poorly in response to re-stimulation and further acquired a T-cell suppressive function. T10G7-act did not directly inhibit proliferation of responder T cells, but formed stable heterotypic clusters with dendritic cells (DC) via CD2 to constrain activation of responder T cells. Together, our data demonstrate that CD43 is a unique and polarizing regulator of T-cell function.P 22869-B11(VLID)311063