Regulatory Type 1 Cells in Glomerulonephritis See article p. 1669

Microbiomes Alter Nucleic Acid Vaccine Efficacy See article p. 1680

Ly6Chi Monocytes Mediate Fibrotic Progression See article p. 1714

In this Top Read, Johnson et al. (p. 1680) elucidated the role of the microbiome in the efficacy of nucleic acid vaccines. Germ-free (GF) and specific pathogen-free (SPF) mice were immunized with either a protein/adjuvant vaccine, a DNA-prime, a DNA-protein-boost regimen, or a single dose mRNA–lipid nanoparticle (LNP) vaccine. Although there was no difference in Ab titers between the GF and SPF mice receiving the protein/adjuvant vaccine, SPF mice showed a decrease in the IL-10 response compared with GF mice, suggesting that the microbiome may impede IL-10 responses following a protein/adjuvant immunization. Altering the microbiome with the addition of either probiotics thought to be immune stimulatory or wild-type fecal transfer did not restore the IL-10 response. The DNA vaccine regimen showed increased Ab titers and IFN-γ responses in GF mice compared with the SPF mice, suggesting that the microbiome may decrease DNA vaccine efficacy. In contrast, the mRNA-LNP vaccines showed enhanced CD8+ T cell responses in SPF mice compared with the GF mice, although no changes were noted for Ab titers or CD4+ T cell responses. These data highlight the complicated interaction between the microbiome and vaccination and demonstrate the need for further research into mechanisms by which the microbiome influences immunity.

Tregulatory type 1 (Tr1) cells are CD4+ and produce IL-10 but lack Foxp3 expression. In this Top Read, Soukou-Wargalla et al. (p. 1669) demonstrate that Tr1 cells were present in the kidney during glomerulonephritis and that these cells may act to ameliorate disease. RNA sequencing of Foxp3neg IL-10+ T cells from the kidneys of nephritic mice revealed seven gene family clusters, two of which had transcriptional profiles similar to Tr1 cells and showed expansion following anti-CD3 treatment. Compared to classical Foxp3+ regulatory T cells, purified kidney Tr1 cells showed similar suppression of effector CD4+ T cells in vitro. Adoptively transferred Tr1 cells were able to increase survival and decrease kidney damage in nephritic mice. Finally, Tr1 cells were identified in kidney biopsies from patients with anti-neutrophil cytoplasmatic Ab-associated glomerulonephritis. These data show the role that Tr1 cells play in glomerulonephritis and demonstrate that they may be a potential target for immunotherapies aiming to prevent kidney damage.

In this Top Read, Larson-Casey et al. (p. 1714) show that inflammatory monocyte recruitment and pulmonary fibrosis (PF) are mediated by exposure to fine particulate matter (PM2.5). Compared with control mice, mice with established PF showed increased collagen deposition and decreased survival. Following exposure to PM2.5, bronchoalveolar lavages (BAL) had increased numbers of Ly6Clo and Ly6Chi monocytes. However, in mice with established PF, there were significantly greater numbers of inflammatory Ly6Chi monocytes. Adoptive transfer of these Ly6Chi monocytes prior to induction of PF resulted in little change in fibrosis following PM2.5 exposure but transfer following induction of PF led to widespread collagen deposition and lung architecture destruction after exposure to PM2.5. Further, fibrosis was decreased in PF mice exposed to PM2.5 when Ly6Chi monocyte recruitment into the lungs was inhibited. Together, these data suggest that Ly6Chi monocytes mediate the progression of fibrosis following environmental pollution exposure. Therapies targeting Ly6Chi monocytes could help slow the progression of PF.