Cell surface expression of the endoplasmic reticular heat shock protein gp96 is phylogenetically conserved

In mammals, the heat shock protein gp96 complexed to antigenic peptides eli cits T cell adaptive immunity. By itself, however, gp96 can evoke responses that are characteristic of innate immunity, Interestingly, this protein, w hich resides in the endoplasmic reticulum, is expressed on the surface of c ertain mouse tumor cells, Given that heat shock proteins are highly conserv ed, we investigated whether the cell sm face expression of gp96 is also evo lutionarily conserved. Our data reveal that gp96, most likely containing th e endoplasmic reticulum retention motif (KDEL), is expressed on the surface of three different Xenopus lymphoid tumor cell lines, each derived from a different spontaneously arising thymic tumor. Levels of expression differ a mong the tumor lines tested, with more immunogenic tumors expressing greate r amounts of surface gp96, Moreover, a high level of gp96 surface expressio n is detectable on a subset of Xenopus normal nontransformed splenic lympho cytes (mainly surface IgM(+) B cells) but not on other normal cells, includ ing macrophages and nucleated erythrocytes, Surface expression of a gp96 pr otein homologue occurs also on some, but not all, T and B cell clones deriv ed from peripheral blood cells of the channel catfish, as well as on lympho cyte-like cells, but not on erythrocytes from the hagfish, a primitive agna than vertebrate lacking markers of an adaptive immune system, gp96 is activ ely directed to and retained on the plasma membrane of Xenopus lymphocytes and tumor cells and hagfish lymphocyte-like cells bg a process that require s vesicular transport. This selective surface expression of gp96 on some im mune cells from different vertebrate classes is consistent with an ancestra l immunological role of gp96 as danger-signaling molecule.