A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation.

The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively modulates regulatory T cell (TREG) differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions.

Oxidative stress disrupts oligodendrocyte maturation.

Periventricular white matter injury (PWMI) is the leading cause of chronic neurologic injury among survivors of preterm birth. The hallmark of PWMI is hypomyelination and a lack of mature, myelinating oligodendrocytes. Oligodendrocytes undergo a well-characterized lineage progression from neural stem cell to mature oligodendrocyte.

Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitis.

Although spontaneous remyelination occurs in multiple sclerosis (MS), the extent of myelin repair is often inadequate to restore normal function. Oligodendrocyte precursors remaining in nonremyelinating MS plaques may be restricted by an inhibitory signal. Bone morphogenetic proteins (BMPs) have been implicated as repressors of oligodendrocyte development and inducers of astrogliogenesis.

BMP signaling mutant mice exhibit glial cell maturation defects.

Bone morphogenetic proteins have been implicated in the development of oligodendrocytes and astrocytes, however, a role for endogenous BMP signaling in glial development has not been demonstrated in a genetic model. Using mice in which signaling via type I BMP receptors Bmpr1a and Bmpr1b have been inactivated in the neural tube, we demonstrate that BMP signaling contributes to the maturation of glial cells in vivo. At P0, mutant mice exhibited a 25-40% decrease in GFAP+ or S100beta+ astrocytes in the cervical spinal cord.

Oligodendrocyte maturation is inhibited by bone morphogenetic protein.

Mature oligodendrocytes myelinate axons in the CNS. The development of the myelin sheath is dependent on the proper maturation of oligodendrocytes from precursors cells, a spatially restricted process that is regulated by inductive and repressive cues. Several members of the bone morphogenetic protein family (BMP2 and 4) have been implicated as repressors of oligodendrocyte development in vitro by shifting oligodendrocyte precursors into the astrocyte lineage.