Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity.

COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses.

Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity.

Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates differentiation of autoimmune T helper (Th) 17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not significantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily administration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases.

JunB Is Critical for Survival of T Helper Cells.

Clonal expansion and differentiation of various T helper subsets, such as Th1, Th2, and Th17 cells, depend on a complex of transcription factors, IRF4 and a BATF-containing AP-1 heterodimer. A major BATF heterodimeric partner, JunB, regulates Th17 differentiation, but the role of JunB in other T helper subsets is not well understood. Here we demonstrate that JunB is required for clonal expansion of Th1, Th2 and Th17 cells. In mice immunized with lipopolysaccharide (LPS), papain, or complete Freund's adjuvant (CFA), which induce predominantly Th1, Th2 and Th17 cells, respectively, accumulation of antigen-primed, Junb-deficient CD4+ T cells is significantly impaired. TCR-stimulated Junb-deficient CD4+ T cells are more sensitive to apoptosis, although they showed largely normal proliferation and cellular metabolism. JunB directly inhibits expression of genes involved in apoptosis, including Bcl2l11 (encoding Bim), by promoting IRF4 DNA binding at the gene locus. Taken together, JunB serves a critical function in clonal expansion of diverse T helper cells by inhibiting their apoptosis.