Abstract
Interleukin-2 (IL-2) is a key regulator of adaptive immune responses but its regulation is incompletely understood. We previously found that PDL1-dependent signals were pivotal for liver sinusoidal endothelial cell-mediated priming of CD8 T cells, which have a strongly reduced capacity to produce IL-2. Here, we show that the expression of the ARF-like GTPase Arl4d is PD-L1-dependently induced in such LSEC-primed T cells, and is associated with reduced IL-2 secretion and Akt phosphorylation. Conversely, Arl4d-deficient T cells overproduced IL-2 upon stimulation. Arl4d-deficiency in CD8 T cells also enhanced their expansion and effector function during viral infection in vivo. Consistent with their increased IL-2 production, Arl4d-deficient T cells showed enhanced development into KLRG1+CD127− short-lived effector cells (SLEC), which is dependent on IL-2 availability. Thus, our data reveal a PD-L1-dependent regulatory circuitry that involves the induction of Arl4d for limiting IL-2 production in T cells.
Highlights
In recent years it has become increasingly clear that the T cell growth factor interleukin-2 (IL-2) exerts multiple functions in regulation of the immune system[1,2]
We have previously shown that during liver sinusoidal endothelial cells (LSEC)-mediated priming of CD8 T cells, which leads to the induction of CD8 T cells incapable of immediate effector function[22,26], insufficient IL-2 production during priming is essential[24]
Quantitative real-time PCR of T cells primed by LSEC, Pdl1−/− LSEC and dendritic cells (DC) confirmed that Arl4d mRNA was potently induced during LSEC-mediated CD8 T cell stimulation (Fig. 1A)
Summary
In recent years it has become increasingly clear that the T cell growth factor interleukin-2 (IL-2) exerts multiple functions in regulation of the immune system[1,2]. IL-2, for instance, is pivotal for both the development of CD4+CD25+ regulatory T cells (Treg)[3,4] and their immune suppressive function. Mature Treg limit T cell responses directly via the consumption of IL-25,6 or indirectly by limiting IL-2 production due to inhibited DC maturation[7]. Is IL-2 availability regulated by co-stimulation or consumption by Treg, its production is actively limited via co-inhibitory programmed-death-1 (PD-1) in T cells[17,18]. During priming of naïve CD8 T cells by liver sinusoidal endothelial cells (LSEC), LSEC-derived PD-L1 signals[22,23] and the resulting limited production of IL-224 are pivotal for the development of liver-primed T cells, which unable to directly mediate effector function[23,25], are capable of memory function providing anti-infectious immunity[26]. Statistical significance was calculated using a oneway ANOVA, * p ≤ 0.05, ** p ≤ 0.01, ***p ≤ 0.001
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
