The Intraepithelial T Cell Response to NKG2D-Ligands Links Lymphoid Stress Surveillance to Atopy

Abstract

Epithelial cells respond to physico-chemical damage with up-regulation of major histocompatbility complex-like ligands that can activate the cytolytic potential of neighboring intraepithelial T cells by binding the activating receptor, NKG2D. The systemic implications of this lymphoid stress-surveillance response, however, are unknown. We found that antigens encountered at the same time as cutaneous epithelial stress induced strong primary and secondary systemic, T helper 2 (T H 2)-associated atopic responses in mice. These responses required NKG2D-dependent communication between dysregulated epithelial cells and tissue-associated lymphoid cells. These data are germane to uncertainty over the afferent induction of T H 2 responses and provide a molecular framework for considering atopy as an important component of the response to tissue damage and carcinogenesis.A conserved feature of T lymphocytes is their subdivision into two main types. One, composed of CD4 + and CD8 + T cells specific for complexes of peptides and major histocompatbility complex (MHC) molecules, has been termed "conventional" and is largely responsible for clonal, pathogen-specific memory responses that are the hallmark of adaptive immunity. The second T cell type, composed of cells expressing the T cell receptor (TCR), is not generally specific for peptide-MHC complexes and may instead recognize cell surface microbial and/or self-encoded moieties, some of which are upregulated through cellular dysregulation. Although T cells exhibit some properties characteristic of adaptive immunity, a predominant function of these "unconventional" Tcells is thought to be lymphoid stress-surveillance because they do not require major clonal expansion, because their functional potentials are preprogrammed during development, and because some may be activated in vivo independently of the TCR, by cytokines or by ligands for activating natural killer (NK) receptors, such as NKG2D (1). Such cells are major components of large but enigmatic tissue-resident Tcell compartments, which include mouse dendritic epidermal T cells (DETCs) and human or mouse intraepithelial lymphocytes (IELs), among which CD4 − CD8 − T cells may also contribute to rapid lymphoid stress-surveillance.Because NK G2D ligands such as Rae-1 (mouse) and MIC class 1 chain-related protein A (MICA) (human) are activated by DNA damage (2) and are frequently expressed by tumor (3,4). However, whether lymphoid stress-surveillance describes a purely local response or whether it affects the systemic immune compartment remains a key question. To investigate this, transgenic Rae-1 expression was induced as described (4) specifically in keratinocytes by a doxycycline (dox)-dependent, bitransgenic (BTg) molecular switch ( fig. S1A). This mode of Rae-1 induction avoids pleiotropic effects of applying agents that induce a stressed state within the epidermis. Rae-1 induction on otherwise normal epithelium promoted rapid morphological rearrangements of DETCs and of epidermal Langerhans cells (LCs), whi...

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

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Persistence of skin-resident memory T cells within an epidermal niche

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Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

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