Differential expression of CD28 and CD94/NKG2 on T cells with identical TCR beta variable regions in primary melanoma and sentinel lymph node

NK cell tolerance is maintained by the interaction of killer inhibitory rec eptors with self MHC class I gene products. A subset of T cells also expres s killer inhibitory receptors, but the functional significance of this is u nclear. Here we demonstrate that the expression of the C-lectinlike killer inhibitory receptor CD94/NKG2 on T cells depends on the state of differenti ation during the immune response to solid tumors. To this end we identified clonally expanded T cells which were present both in the sentinel lymph no de of primary melanoma, as well as in the tumor itself. In situ characteriz ation of such T cell clonotypes revealed that within the early stages of T cell activation, i.e. priming in the lymph node, T cells did not express CD 94/NKG2 whereas the same T cell clones expressed high levels of CD94/NKG2 h aving reached the effector stale at the tumor site. Moreover, while the phe notype of these T cell clones was CD28(high) in, the lymph node only CD28(l ow) or CD28(-)T cells were found within the tumor. Double staining for CD94 and CD28 conformed that CD94/NKG2- expressing cells were preferentially CD 28(-). Thus, T cells may down-regulate CD28 and up-regulate NK receptors as consequence of prolonged activation for cytolytic effector function. It is likely that NK receptors are involved in peripheral regulatory mechanisms avoiding overwhelming immune responses and immunopathology, particularly in situations of long-lasting immune activation.