Contact sensitizers trigger human CD1‐autoreactive T‐cell responses

Abstract

Allergic contact dermatitis is a primarily T-cell-mediated inflammatory skin disease induced by exposure to small molecular-weight haptens, which covalently bind to proteins. The abundance of cutaneous T cells that recognize CD1a antigen-presenting molecules raises the possibility that MHC-independent antigen presentation may be relevant in some hapten-driven immune responses. Here we examine the ability of contact sensitizers to influence CD1-restricted immunity. Exposure of human antigen-presenting cells such as monocyte-derived dendritic cells and THP-1 cells to the prototypical contact sensitizer dinitrochlorobenzene potentiated the response of CD1a- and CD1d-autoreactive T cells, which released a vast array of cytokines in a CD1- and TCR-dependent manner. The potentiating effects of dinitrochlorobenzene depended upon newly synthesized CD1 molecules and the presence of endogenous stimulatory lipids. Further examination of a broad panel of contact sensitizers revealed 1,4-benzoquinone, resorcinol, isoeugenol and cinnamaldehyde to activate the same type of CD1-restricted responses. These findings provide a basis for the antigen-specific activation of skin-associated CD1-restricted T cells by small molecules and may have implications for contact sensitizer-induced inflammatory skin diseases.

Of self‐lipids, CD1‐restricted T cells, and contact sensitization

“…A different small representative set of CD1a T cells, CD1d‐restricted invariant NKT cells (some of which autoreactive) or γδ T cells, did not react to DNCB, implying that the TCR clonotype is important for this process. Consistent with this, and also with the published data on MHC‐restricted T‐cell responses, T‐cell stimulation by DNCB required CD1 presentation and TCR recognition . Interestingly, DNCB‐induced autoreactivity required prolonged treatment (>12 h) of metabolically active APCs, CD1 transport to the membrane and loading of selected species of “cryptic” agonist self‐lipids upon CD1 biosynthesis, implying an effect of the chemical on the binding of specific lipids on newly synthesized molecules.…”

“…(i) CD1 molecules bind self‐lipids at steady state and do not normally stimulate T‐cell responses; Some CSs, such as the plant‐derived pentadecylcatechol (C15:2) urushiol, directly bind the groove of CD1a on epidermal Langerhans cells and are recognized by specific TCRs ; (iii) The house dust mite (HDM) Dermatophagoides represents the CS that produces phoshopolipase A2 (PLA 2 ), which acts on skin‐derived phospholipids, generating new endogenous self‐lipids that in turn bind CD1a on Langerhans cells and activate CD1a‐restricted self‐reactive T cells ; (iv) As suggested by Betts et al. , chemical CSs, such as DNCB, may bind CD1a or CD1d molecules upon biosynthesis and promote, in some as yet unknown way, the formation of stimulatory complexes made of CD1 molecules with a set of cryptic self‐lipids expressed by particular APCs (myeloid cells such as moDCs or acute myeloid leukemia cell lines, but not B lymphoid or epithelial cells).…”

“…In this issue of European Journal of Immunology , a new study by Betts et al. further advances our understanding of the immunological mechanisms subtending contact sensitization, by showing that common CS xenobiotics can stimulate the response of a different class of T cells that are specific for self‐lipids restricted by CD1 molecules. CD1a, b, c (group 1) and CD1d (group 2) are MHC class I‐related molecules specialized in the presentation of microbial and cell‐endogenous lipids to T cells .…”

“…Building on this premise, Betts et al. addressed whether CSs may recruit lipid‐specific CD1‐restricted T‐cell activation in vitro, and found that the classic CS DNCB further enhanced the responses of a selected CD1a self‐reactive T‐cell clone upon recognition of CD1a‐expressing myeloid APCs in vitro . Furthermore, DNCB induced autoreactivity of a CD1d‐restricted noninvariant NKT cell, suggesting that DNCB may unleash an otherwise silent self‐reactivity.…”

“…The authors went on to show that the stimulatory effects of CSs for CD1 self‐reactive T cells are not restricted to DNCB, as other common xenobiotics were stimulatory for either CD1d‐restriced (resorcinol, isoeugenol, cinnamaldehyde) or CD1 a restricted (1,4‐benzoquinone) T‐cell clones, but not both . These results have several interesting implications: i .…”