CTLA‐4 function has been intensively highlighted with a focus on the extracellular domain of CTLA‐4 because of its ability to bind to B7, which is expressed by antigen presenting cells, competing with CD28.[6a,b] A fusion protein of the extracellular domain of CTLA‐4 and the Fc region, named CTLA‐4‐Ig, was the first immune checkpoint regulatory drug approved for rheumatoid arthritis therapy.[17] We hypothesized that CTLA‐4‐Ig would inhibit T cell activation but have no effect on Treg function, in contrast to the cytoplasmic domain of CTLA‐4 (Figure 5a). Here, CD28 is linked to rheumatoid arthritis.