Alloantigen-specific T-cell anergy induced by human keratinocytes is abrogated upon loss of cell-cell contact.

Abstract

The activation of primary human T cells largely depends on the expression of both major histocompatibility complex (MHC) class II and B7 molecules on antigen-presenting cells (APC), whereas APC expressing HLA class II but not B7 antigens are expected to induce anergy. According to this concept, interferon-gamma (IFN-gamma)-activated keratinocytes (KC) expressing HLA class II but not B7 costimulatory antigens should be able to induce anergy. However, in terms of anergy versus activation contradicting data have been published on the outcome of interaction between T cells and human KC. In addition, it has been shown that human KC can express a B7-like molecule with unknown function, whereas MHC expression may be functionally impaired. To evaluate this item we transfected the human A431 KC cell line with B7-1 coding sequences and up-regulated HLA-DR by treatment with IFN-gamma, yielding A431DR,B7-1 cells. Irradiated A431DR,B7-1 cells were found to be capable of inducing vigorous proliferative primary T-cell responses in resting allogeneic T cells, whereas A431DR cells could induce proliferation only when interleukin-2 (IL-2) was added. These data indicate that KC can present alloantigens, and that lack of costimulatory molecules on KC is the main reason why these cells cannot induce primary T-cell responses. Surprisingly, however, no evidence could be obtained of stable anergy induction by A431DR cells, as T cells contacted with A431DR cells and then transferred to A431DR,B7-1 cells clearly demonstrated alloresponsiveness. T-cell non-responsiveness was maintained only when T cells remained in contact with A431DR cells. These data indicate that, despite expression of HLA class II in the absence of B7 costimulatory molecules, human KC cannot induce stable anergy but rather induce short-term anergy in primary resting T cells.