Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases

- SEMA4D/CD100 exists both as a transmembrane and a soluble molecule.
- SEMA4D has important roles in regulating both innate and adaptive immune responses.
- sSEMA4D levels are increased in many autoimmune and infectious diseases.
- SEMA4D is a potential novel immune biomarker for monitoring disease activity.
- Blocking antibodies against SEMA4D are currently evaluated in clinical trials.

SEMA4D/CD100 is a homodimeric protein belonging to the semaphorin family of axonal guidance proteins. Semaphorin family members have received increased attention lately due to their diverse functions in the immune system. SEMA4D was the first semaphorin described to have immune functions and serves important roles in T cell priming, antibody production, and cell-to-cell adhesion. Proteolytic cleavage of SEMA4D from the cell surface gives rise to a soluble fragment of SEMA4D (sSEMA4D). Similar to the transmembranal form, sSEMA4D is thought to have immunoregulatory properties. While the exact mechanisms responsible for SEMA4D shedding remain to be elucidated, emerging data have revealed associations between elevated systemic sSEMA4D levels and severity of infectious and inflammatory diseases. This review summarizes the literature concerning sSEMA4D and discusses its potential as a novel prognostic immune-biomarker and potential target for immunotherapy.