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

Abstract

SUMMARYThe activation of primary human T cells largely depends on the expression of both major histocompatibility complex (MHC) class 11 and B7 molecules on antigen-presenting cells (APC), whereas APC expressing HLA class I1 but not B7 antigens are expected to induce anergy. According to this concept, interferon-y (IFN-y)-activated keratinocytes (KC) expressing HLA class I1 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 upregulated HLA-DR by treatment with IFN-y, yielding A43 IDRsB7-' cells. Irradiated A43 lDRSB7-l cells were found to be capable of inducing vigorous proliferative primary T-cell responses in resting allogeneic T cells, whereas A43 lDR 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 A43IDRsB7-' 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 I1 in the absence of B7 costimulatory molecules, human KC cannot induce stable anergy but rather induce short-term anergy in primary resting T cells.

The Epidermis as an Adjuvant

“…Various studies documented that KCs do not normally express the co-stimulatory molecules CD80/86 (Black et al, 2007), and thus they are unlikely to prime naïve T cells in a steady state (Gaspari et al, 1988;Otten et al, 1996;Laning et al, 1997). Consistently, early reports have indicated that class-II-mediated presentation of antigen by KCs results in tolerance or anergy of T cells (Gaspari et al, 1988;Bal et al, 1990).…”

Keratinocytes Induce Local Tolerance to Skin Graft by Activating Interleukin-10–Secreting T Cells in the Context of Costimulation Molecule B7-H11

“…1 and 4C) suggests the involvement of indirect instead of direct recognition of alloantigens by T cells (23,27). It is not clear, however, whether keratinocytes are capable of processing and presenting antigen peptides in context with major histocompatibility complex class II molecules to activate T-cell-mediated alloreactions, although some data did suggest such activity of keratinocytes when B7 gene was introduced (28). Bal and colleagues also reported that human keratinocytes could induce an influenza hemagglutinin-specific immune nonresponsiveness by antigen presentation in a DR-restricted manner (29).…”

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4+ and CD8+ T cells

“…The expression of B7-H1 by human keratinocytes has been implicated in the induction of tolerance by activation of IL-10-producing T cells [9]. This tolerance is not stable, and appears to be dependent on cell-cell contact [10]. Furthermore, keratinocytes have been shown to be unable to stimulate T cell lines to recall antigen [11] or stimulate the proliferation of allogeneic T cells [12].…”