Top Reads

In this Top Read, Batra et al. (p. 2840) demonstrate that transplanted islet cells modified to transiently display PD-L1 have sustained survival in allogeneic hosts and can modulate local tolerance. Islet cells were isolated from allogeneic donors and modified by physically binding a chimeric protein of PD-L1 with core streptavidin (SA-PDL1) onto their surface. Binding of SA-PDL1 to the surface of the islets did not impact their ability to secrete insulin in response to glucose stimulation. In conjunction with a 15 d rapamycin regimen, transplanted SA-PDL1 islets had sustained survival >90% at 100 d posttransplantation and were functional long-term. Although allograft recipients generated a systemic response to donor Ags, analysis of intragraft gene expression 3 d posttransplantation showed that mice receiving SA-PDL1 islets plus rapamycin had an increase in anti-inflammatory gene transcripts, a decrease in proinflammatory gene transcripts, and increased expression of markers for M2 macrophages. Compared with mice receiving only rapamycin, islet draining lymph nodes from mice receiving SA-PDL1 plus rapamycin had a higher ratio of regulatory to effector T cells. Depletion of regulatory T cells following transplantation resulted in an increase in blood glucose levels. Together, these data suggest that SA-PDL1 on transplanted islet cells synergizes with rapamycin immediately posttransplantation to alter the local immune environment in favor of graft survival. This strategy could be harnessed to enhance survival of islet graphs for the treatment of type 1 diabetes.

Despite numerous studies implicating complement in lupus nephritis (LN), the precise mechanisms resulting in kidney injury remains unknown. In this Top Read, Skopelja-Gardner et al. (p. 2627) generated polygenic murine models embodying three key genetic alterations driving LN: 1) Mfge8-deficiency (Mfge8^−/−), leading to defective clearance of apoptotic cells (AC); 2) the Sle1 interval, leading to anti-chromatin autoantibodies; and 3) either C1q (C1q^−/−) or C3 (C3^−/−) deficiency, leading to low complement levels. Whereas anti-chromatin autoantibodies and defective clearance of AC were not sufficient to induce clinical nephritis, the addition of either C1q or C3 deficiency (C1q^−/− triple-mutant [TM] or C3^−/−TM) promoted spontaneous glomerulonephritis similar to that found in LN patients. Interestingly, both TM strains had increases in autoantibody titers, Ag spreading, and IgG deposition in the kidneys. Despite complement deficiencies in both TM strains, the authors observed assembly of the pathogenic terminal complement membrane attack complex (MAC). In C1q^−/− TM mice, colocalization of MASP-2 and C3 in the kidney indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Using a model of immune complex (IC)-mediated nephritis, the authors demonstrated that thrombin contributed to complement activation and kidney damage in the absence of C3. Consistent with this, enhanced fibrin deposition in the kidneys of C3^−/−TM, but not C1q^−/− TM, mice revealed a role for thrombin activation in low C3 states. Thus, these novel mouse models reveal the mechanisms driving LN and provide targets for therapeutic intervention.

The role of STAT1 phosphorylation at serine 727 (STAT1-pS727) in eliciting innate immune responses is well known. However, the requirement of STAT1-pS727 in autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, autoantibody production, and systemic lupus erythematosus (SLE) pathogenesis remains unknown. In this Top Read, Chodisetti et al. (p. 2641) demonstrate that a STAT1-S727A mutant in autoimmune-prone B6.Sle1b mice promotes autoimmune AFC and GC responses, thereby driving autoantibody production and the development of SLE. Of note, STAT1-pS727 was not required for GC, T follicular helper cell (Tfh), and Ab responses to foreign Ags, including pathogen-derived Ags, and for gut microbiota and dietary Ag–driven GC and Tfh responses in B6.Sle1b mice. Generation of B cell–specific bone marrow (BM) chimaras revealed that the role of STAT1-pS727 in promoting autoimmune AFC, GC, and Tfh responses is B cell intrinsic. In addition, the authors demonstrated that STAT1-pS727 promoted TLR7-accelerated SLE pathogenesis and lupus nephritis development. Thus, this study reveals a previously unrecognized mechanism for regulation of systemic autoimmune and antipathogen responses by STAT1-pS727, a new candidate target for SLE therapeutics.

In this Top Read, Nieto et al. (p. 2808) show that activation of 5-HT_2B, a serotonin receptor expressed by IL-10–producing human macrophages, stimulates aryl hydrocarbon receptor (AhR) in human macrophages. 5-HT_2B mediates many pathological conditions and, as such, is an off-target of many pharmaceuticals. The authors demonstrated that 5-HT_2B stimulation modified transcriptional expression of 758 genes in macrophages. In contrast, 207 of these genes were unaffected by the addition of a 5-HT_2B antagonist, indicating both 5-HT_2B–dependent and 5-HT_2B–independent mechanisms of gene regulation. Although 5-HT_2B stimulation did not alter the basal cytokine levels produced by macrophages, it reduced production of TNF-α and increased release of CCL2 in LPS-stimulated macrophages. Increased expression of AhR target genes following 5-HT_2B agonist treatment indicated that 5-HT_2B activation could influence AhR-regulated genes. The effect of the 5-HT_2B agonist on AhR target gene transcription was blocked by antagonists for both 5-HT_2B and AhR. Finally, treatment of human macrophages with serotonin resulted in a dose-dependent enhancement of AhR target genes, indicating that serotonin modulates transcription profiles via 5-HT_2B–induced activation of AhR. These data demonstrate the existence of a functional serotonin/5-HT_2B/AhR axis in human macrophages, suggesting that serotonin may potentiate immune and biological responses to xenobiotics.