in 1987 , researchers hunting for cytotoxic cell surface molecules isolated a cdna from activated cd8 t cells and called it cytotoxic t cell antigen ( ctla)-4 ( 2 ) .
genetic studies provided a clue that connected ctla-4 to t cell costimulation : ctla-4 and cd28 both mapped to the same chromosomal neighborhood and shared a high degree of sequence similarity ( 3 ) .
this information caught the attention of jeffrey ledbetter and peter linsley at the bristol - myers squibb research institute ( seattle , wa ) . at the time , their group was studying b7-cd28 interactions using a soluble version of cd28 that lacked transmembrane and intracellular domains .
the soluble cd28 protein worked just as well as the cell - attached version in binding b7 ( 4 ) .
the team hedged their bets on the similarities between ctla-4 and cd28 and tested whether ctla-4 also bound b7 .
soluble ctla-4 turned out to bind b7 with 20-fold higher avidity than the soluble cd28 protein , establishing ctla-4 as a second receptor for b7 .
the group published these results in the journal of experimental medicine in 1991 ( 5 ) .
it now seemed that ctla-4 was a third switch in what was previously thought to be a two - switch circuit for t cell activation .
but whether it promoted or jammed the circuit was a contentious issue for several more years .
the debate arose because in vitro assays of costimulation - dependent t cell proliferation offered multiple interpretations .
but when soluble ctla-4 was added to the mix , this proliferation was strongly inhibited ( 5 ) . one interpretation of this finding was that the soluble ctla-4 blocked the binding of b7 to the ctla-4 on the t cells . in this model ,
this conclusion was supported when the group showed that antibodies to ctla-4 enhanced cd28-stimulated proliferation ( 6 ) . a second interpretation , however , was that soluble ctla-4 might block proliferation by gumming up b7 's interaction with cd28 . and the ctla-4 antibody might enhance proliferation not because it stimulates clta-4 's proliferative power , but because it blocks ctla-4 's negative signal .
this alternative role for ctla-4 was supported by the work of james allison and his team at the university of california ( berkeley , ca ) , which was also published in the jem ( 7 ) .
this group studied cross - talk among tcr , cd28 , and ctla-4 by cross - linking these receptors .
t cells proliferated when the tcr was linked to cd28 , but not with ctla-4 .
t cell proliferation was greatly reduced when all three receptors were cross - linked simultaneously , suggesting that ctla-4 inhibits cd28 costimulation .
the generation of ctla-4 knock - out mice finally put the conflict to rest . these animals
develop a fatal t cell proliferative disorder , as their t cells lack the brakes to hold them in check ( 8) .
one benefit of enhancing t cell responses via ctla-4 blockade is the strengthening of antitumor immunity .
allison 's team found that tumor - transplanted mice injected with antibodies that block ctla-4 activity rejected several different types of tumors and had long - lasting antitumor immunity ( 9 ) .
human anti - ctla-4 mabs are now in phase iii clinical trials against melanoma and renal carcinomas .
the t cell  inhibiting soluble ctla-4 originally defined by linsley and ledbetter is now used to treat autoimmune diseases such as rheumatoid arthritis .
 ctla-4 was first identified in 1991 as a second receptor for the t cell costimulation ligand b7 . 
 uncertainties about its biological function plagued the early years after its discovery until 1995 , when it was confirmed to be an inhibitor of t cell responses . 
 ctla-4 has since scored in the clinic as a target for antitumor therapy and as a soluble inhibitor of autoimmunity . 
Another T cell switch
but on or off?
CTLA-4 in the clinic