A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.
CTLA-4, expressed by activated T cells, transduces an inhibitory signal. We show here that PCR amplification of the coding sequence of CTLA-4 in nonstimulated human T lymphocytes results in the amplification of two transcripts of 650 and 550 bp. Sequencing shows that the larger form codes for membrane CTLA-4 and the 550-bp transcript is a spliced variant in which exon 2 coding for the transmembrane region is deleted. This spliced cDNA has been named CTLA-4delTM. The splicing induces a frame shift which results in the addition of 22 extra amino acids before a translational termination. Activation of T cells with phorbol 12-myristate 13-acetate plus ionomycin or anti-CD3 plus anti-CD28 monoclonal antibodies induces a suppression of CTLA-4delTM mRNA expression associated with a preferential expression of the membrane CTLA-4 mRNA, showing that CTLA-4delTM mRNA expression is restricted to nonactivated T cells. A soluble immunoreactive form of CTLA-4 was detected in the serum of 14 / 64 healthy subjects. These results suggest that nonstimulated T cells may constitutively produce a soluble form of CTLA-4 which may have an important role in the regulation of immune homeostasis.
Magistrelli
G
G
Centre d'Immunologie Pierre Fabre, Saint Julien en Genevois, France.
Jeannin
P
P
Herbault
N
N
Benoit De Coignac
A
A
Gauchat
J F
JF
Bonnefoy
J Y
JY
Delneste
Y
Y
D000069594:Abatacept; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000069594:Abatacept