Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

Abstract

An inappropriate cross talk between activated T lymphocytes infiltrating the CNS and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases. To mimic this deleterious cross talk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain. We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions. These effects were reminiscent of those induced by brain semaphorin on neural cells. Blockade by specific Abs of soluble CD100 (sCD100)/semaphorin 4D released by activated T cells, or treatment with rsCD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, most likely through receptors of the plexin family. The specific presence of sCD100 in the cerebrospinal fluid and of CD100-expressing T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed to the potential pathological effect of sCD100 in the CNS. Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy.

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…Oligodendrocyte progenitors and oligodendrocytes express a broad spectrum of semaphorins, neuropilins, plexins, and CRMPs (Cohen et al, 2003;Goldberg et al, 2004;Moreau-Fauvarque et al, 2003;Ricard et al, 2000Ricard et al, , 2001Spassky et al, 2002). Furthermore, semaphorins belonging to different subclasses, including class 3, can induce process retraction in oligodendrocyte progenitors and oligodendrocytes and can also orient the migration of oligodendrocyte progenitors in vitro (Cohen et al, 2003;Giraudon et al, 2004;Goldberg et al, 2004;Ricard et al, 2000Ricard et al, , 2001. In addition to postnatal and adult oligodendrocytes, we report here dramatically increased MICAL-1 and -3 expression in oligodendrocytes immediately adjacent to sites of adult spinal cord injury.…”

Regulation of immune cell responses by semaphorins and their receptors

“…Sema4D-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) due to impaired antigen-specific T-cell responses in the draining lymph nodes and attenuated inflammation in the central nervous system. 51 In addition, T-cell-derived Sema4D has been implicated in the collapse of process extension of immature oligodendrocytes and the death of immature neural cells in the spinal cords of patients with human T-cell lymphotropic virus type 1-associated myelopathy 52 ( Table 1). Figure 1 Representative immune semaphorins and their receptors in lymphoid and non-lymphoid cells.…”

Saturation monitoring of VX15/2503, a novel semaphorin 4D‐specific antibody, in clinical trials

“…The three reportable results generated are: 1 the percent saturation of SEMA4D on peripheral T cells; 2 the fold over isotype (FOI) for VX15/2503; and 3 FOI for mAb 2282‐biotin. The geometric mean fluorescence intensity (GMFI) derived from the SA‐APC FL4 for each tube was used to calculate percent saturation and FOI using the following equations: $\text{Percent} \text{Saturation} = | \frac{\left(\mathrm{B}‐\mathrm{A}\right)}{\left(\mathrm{C}‐\mathrm{A}\right)} \times 100|$ $\mathrm{normalV}\mathrm{normalX}15/2503 \text{FOI} = \frac{\mathrm{normalC}}{\mathrm{normalA}}$ $\text{mAb} 2282‐\text{biotin} \text{FOI} = \frac{\mathrm{normalE}}{\mathrm{normalD}}$where:…”

“…Semaphorins consist of a family of soluble and transmembrane proteins, which function in axonal‐guidance, immune cell regulation, vascular growth, and tumor progression 1, 2, 3. They guide migration 4, 5, 6 and cytoskeletal changes in endothelial, immune, and tumor cells within the tumor microenvironment (TME).…”

“…Anti‐SEMA4D has been shown to attenuate EAE in multiple rodent models 15, 16. In addition to the involvement with the immune response to CNS antigens, SEMA4D may play an important role in several other potentially pathogenic CNS processes, including migration of oligodendrocyte precursor cells, oligodendrocyte survival 1, remyelination 16 and the integrity of the neurovascular unit comprised of endothelial cells, astrocytes and pericytes 17.…”