T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX.

Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific immunoglobulin G (IgG), and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4(+) CXCR5(+) T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.

B cells limit repair after ischemic acute kidney injury.

There is no established modality to repair kidney damage resulting from ischemia-reperfusion injury (IRI). Early responses to IRI involve lymphocytes, but the role of B cells in tissue repair after IRI is unknown. Here, we examined B cell trafficking into postischemic mouse kidneys and compared the repair response between control (wild-type) and muMT (B cell-deficient) mice with and without adoptive transfer of B cells. B cells infiltrated postischemic kidneys and subsequently activated and differentiated to plasma cells during the repair phase. Plasma cells expressing CD126 increased and B-1 B cells trafficked into postischemic kidneys with distinct kinetics. An increase in B lymphocyte chemoattractant in the kidney preceded B cell trafficking. Postischemic kidneys of muMT mice expressed higher IL-10 and vascular endothelial growth factor and exhibited more tubular proliferation and less tubular atrophy. Adoptive transfer of B cells into muMT mice reduced tubular proliferation and increased tubular atrophy. Treatment with anti-CD126 antibody increased tubular proliferation and reduced tubular atrophy in the late repair phase. These results demonstrate that B cells may limit the repair process after kidney IRI. Targeting B cells could have therapeutic potential to improve repair after IRI.

Glucose ingestion during endurance training in men attenuates expression of myokine receptor.

Glucose ingestion during exercise attenuates the release of the myokine interleukin-6 (IL-6) from working skeletal muscle, which results in a diminished increase in plasma IL-6. Interleukin-6 receptor alpha (IL-6Ralpha) expression in skeletal muscle is induced by acute exercise, mediated in part by an increased IL-6 concentration in the bloodstream. We hypothesized that endurance training would increase the density of IL-6Ralpha in skeletal muscle and that glucose ingestion would attenuate the effect. Nine subjects performed 10 weeks of one-legged knee-extensor training. They trained one leg (Glc-leg) while ingesting a glucose solution (Glc) and ingested a placebo (Plc) while training the other leg (Plc-leg). Endurance training increased peak power by 14% and reduced the exercise-induced gene expression of IL-6 and IL-6Ralpha in skeletal muscle and IL-6 plasma concentration. The IL-6Ralpha density increased to a lesser extent in the Glc-leg, suggesting that glucose ingestion attenuates the effect of training on IL-6Ralpha by blunting the IL-6 response. We conclude that glucose ingestion during endurance training attenuates the increase in IL-6Ralpha density.

Knockdown of the interleukin-6 receptor alpha chain of dendritic cell vaccines enhances the therapeutic potential against IL-6 producing tumors.

Tumor microenvironment has emerged as one of the major obstacles against the clinical efficacy of dendritic cell (DC) vaccines. Tumor-derived IL-6 may inhibit the differentiation of hematopoietic progenitor cells into DCs and suppress DC maturation, rendering DCs tolerogenic. We hypothesized that silencing the IL-6 receptor alpha chain (IL-6Rα) would restore the functional competence of DC vaccines in mice with an IL-6-producing TC-1 tumor, and eventually give rise to protective immunity. We found that the IL-6Rα knockdown-DC vaccine significantly enhanced the frequency of tumor-specific CD8(+) CTLs-producing effector molecules such as IFN-γ, TNF-α, FasL, perforin, and granzyme B, and generated more CD8(+) memory T cells, leading to the substantially prolonged survival of TC-1 tumor-bearing mice.