This work was supported in part by funding from the German Research Foundation (DFG) for the Cluster of Excellence REBIRTH (from Regenerative Biology to Reconstructive Therapy; EXC 62).
Semaphorin 7A protein variants differentially regulate T-cell activity
Article first published online: 31 JUL 2012
© 2012 American Association of Blood Banks
Volume 53, Issue 2, pages 270–283, February 2013
How to Cite
Gras, C., Eiz-Vesper, B., Seltsam, A., Immenschuh, S., Blasczyk, R. and Figueiredo, C. (2013), Semaphorin 7A protein variants differentially regulate T-cell activity. Transfusion, 53: 270–283. doi: 10.1111/j.1537-2995.2012.03812.x
- Issue published online: 5 FEB 2013
- Article first published online: 31 JUL 2012
- Received for publication August 18, 2011; revision received February 21, 2012, and accepted April 17, 2012.
BACKGROUND: Semaphorin 7A (Sema7A) carries the John-Milton-Hagen human blood group antigen on red blood cells and shows molecular diversity. It is known that Sema7A has immunomodulatory functions, but its regulatory effects on T-cell activation are not completely understood. In this study, the functional role of the R461C Sema7A polymorphism on T-cell responses was investigated.
STUDY DESIGN AND METHODS: Soluble recombinant wild-type Sema7A (Sema7A_wt) and its R461C variant (Sema7A_R461C) were produced in human embryonic kidney cells. Specific assays were performed to determine the effects of Sema7A_wt and Sema7A_R461C on T-cell activation in terms of proliferation, phenotypic alterations, granzyme B transcript levels, and secretion of proinflammatory cytokines.
RESULTS: Sema7A_wt did not affect T-cell activity, but Sema7A_R461C led to marked antigen-independent activation of T cells. In the presence of antigen stimulation, Sema7A_R461C had a major costimulatory effect on T-cell response. Upon Sema7A_R461C stimulation, CD4+ T cells strongly proliferated and exhibited a cytotoxic phenotype with significant up regulation of granzyme B transcripts (up to 220-fold), even in the absence of antigen stimulation. Antibody blocking studies indicated that Sema7A_R461C-mediated T-cell activation is largely β1 integrin dependent.
CONCLUSION: These data demonstrate that Sema7A_R461C, unlike wild-type Sema7A, causes differential regulation of T-cell responses. Since Sema7A has important immunomodulatory functions in inflammatory responses, it might play a key role in autoimmune diseases and other major disorders. Further studies are needed to elucidate the regulatory role of Sema7A and its variants.