Programmed death receptor 1 (PD-1) ligand Fc fusion proteins reduce T-cell proliferation in vitro independently of PD-1.

Programmed death receptor 1 (PD-1) is an inhibitory receptor on T cells shown to restrain T-cell proliferation. PD-1 immune checkpoint blockade has emerged as a highly promising approach in cancer treatment. Much of our understanding of the function of PD-1 is derived from in vitro T-cell activation assays. Here we set out to further investigate how T cells integrate inhibitory signals such as PD-1 in vitro using the PD-1 agonist, PD-1 ligand 1 (PD-L1) fusion protein (PD-L1.Fc), coimmobilized alongside anti-CD3 agonist monoclonal antibody (mAb) on plates to deliver PD-1 signals to wild-type and PD-1-/- CD8+ T cells. Surprisingly, we found that the PD-L1.Fc fusion protein inhibited T-cell proliferation independently of PD-1. This PD-L1.Fc inhibition was observed in the presence and absence of CD28 and interleukin-2 signaling. Binding of PD-L1.Fc was restricted to PD-1-expressing T cells and thus inhibition was not mediated by the interaction of PD-L1.Fc with CD80 or other yet unknown binding partners. Furthermore, a similar PD-1-independent reduction of T-cell proliferation was observed with plate-bound PD-L2.Fc. Hence, our results suggest that the coimmobilization of PD-1 ligand fusion proteins with anti-CD3 mAb leads to a reduction of T-cell engagement with plate-bound anti-CD3 mAb. This study demonstrates a nonspecific mechanism of T-cell inhibition when PD-L1.Fc or PD-L2.Fc fusion proteins are delivered in a plate-bound coimmobilization assay and highlights the importance of careful optimization of assay systems and reagents when interpreting their influence on T-cell proliferation.

Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain.

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.

Axonal degeneration in multiple sclerosis: defining therapeutic targets by identifying the causes of pathology.

Current therapeutics in multiple sclerosis (MS) target the putative inflammation and immune attack on CNS myelin. Despite their effectiveness in blunting the relapse rate in MS patients, such therapeutics do not prevent MS disease progression. Importantly, specific clinical dilemma arises through inability to predict MS progression and thereby therapeutically target axonal injury during MS, limiting permanent disability. The current review identifies immune and neurobiological principles that govern the sequelae of axonal degeneration during MS disease progression. Defining the specific disease arbiters, inflammatory and autoimmune, oligodendrocyte dystrophy and degenerative myelin, we discuss a basis for a molecular mechanism in axons that may be targeted therapeutically, in spatial and temporal manner to limit axonal degeneration and thereby halt progression of MS.