title: Semaphorin 7A protein variants differentially regulate T-cell activity.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors: Christiane
authors: C
authors: Gras
authors: Britta
authors: B
authors: Eiz-Vesper
authors: Axel
authors: A
authors: Seltsam
authors: Stephan
authors: S
authors: Immenschuh
authors: Rainer
authors: R
authors: Blasczyk
authors: Constança
authors: C
authors: Figueiredo
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics* / Q000378:metabolism; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D017252:CD3 Complex; D058851:GPI-Linked Proteins; D011994:Recombinant Proteins; C118753:SEMA7A protein, human; D039961:Semaphorins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048052:Mitogen-Activated Protein Kinase 3