HUMAN CTLA-4 IS EXPRESSED IN-SITU ON T-LYMPHOCYTES IN GERMINAL-CENTERS, IN CUTANEOUS GRAFT-VERSUS-HOST DISEASE, AND IN HODGKINS-DISEASE

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) is a molec ule expressed on in vitro activated T cells, CTLA-4 shares important s equence homology with CD28 and binds to the same ligands, CD80 (B7-1) and CD86 (B7-2), CTLA-4 probably functions as a negative regulator of T lymphocyte activation in the mouse, although this remains to be prov en for human T lymphocytes, We have developed new monoclonal antibodie s against human CTLA-4 and have investigated the in situ expression of CTLA-4 in a wide variety of normal and pathological human tissues exp ressing CD80 and CD86. As revealed in this study, CTLA-4 is expressed on thymocytes in thymic medulla, on a subset of CD4(+) T lymphocytes i n germinal centers of follicular hyperplasia, on T cells, mainly CD8(), infiltrating skin affected by graft-versus-host disease, and on T c ells, mainly CD4(+) infiltrating Hodgkin's disease lesions, In immunoe lectron microscopy, CTLA-4 was found on the plasma membrane as well as in the hyaloplasm and cytoplasmic vesicles, in agreement with its pat tern of expression on in vitro activated T cells, Interestingly, no or at most scarce expression of CTLA-4 was found in granulomatous lymph nodes, T-cell-mediated inflammatory diseases, or non-Hodgkin's lymphom as, regardless of their expression of CD80 or CD86, Thus, expression o f CTLA-4 appears to be induced in selective pathological conditions in vivo, The pathways leading to selective induction of CTLA-4 and its r ole in the pathophysiology of these conditions need to be further inve stigated.