In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption.
ABSTRACT Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN.
Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug.
We immunohistochemically investigated in vivo dynamics of T-cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions.
Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer-like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin-15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years).
Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.
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ABSTRACT: Previous work has shown that memory-phenotype CD44(hi) CD8(+) cells are controlled by a cytokine, interleukin (IL)-15. However, the dependency of CD44(hi) CD8(+) cells on IL-15 is partial rather than complete. Here, evidence is presented that CD44(hi) CD8(+) cells comprise a mixed population of IL-15-dependent and IL-15-independent cells. The major subset of CD122(hi) CD44(hi) CD8(+) cells is heavily dependent on IL-15 by three different parameters, namely (1) "bystander" proliferation induced via IFN-induced stimulation of the innate immune system, (2) normal "background" proliferation, and (3) T cell survival; IL-15 dependency is most extreme for the Ly49(+) subset of CD122(hi) CD44(hi) CD8(+) cells. In contrast to CD122(hi) cells, the CD122(lo) subset of CD44(hi) CD8(+) cells is IL-15 independent; likewise, being CD122(lo), CD44(hi) CD4(+) cells are IL-15 independent. Thus, subsets of memory-phenotype T cells differ radically in their sensitivity to IL-15.Journal of Experimental Medicine 11/2002; 196(7):935-46. · 13.21 Impact Factor
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ABSTRACT: Fixed drug eruption is a distinct variant of drug-induced dermatoses characterized by their relapse in the same location after the administration of the causative drug. We have recently shown that intraepidermal CD8+ T cells phenotypically resembling effector memory T cells are greatly enriched in the resting lesions of FDE. Although effector memory T cells have been implicated as the mediators of protection in epithelial tissues, our observation raises an alternative possibility that improper, enhanced or uncontrolled activation of intraepidermal T cells could contribute to severe tissue injury. Until recently, however, their detrimental effects on epithelial tissues have rarely been examined. The focus of this review is on how intra-epidermal T cells originally evolved to protect tissue integrity can exert an opposite action that is deleterious to the host. Because those T cells residing in the lesions, upon activation, can rapidly produce large amounts of IFN-gammaepsilon followed by localized epidermal injury, their activation is probably essential for the initiation of deleterious inflammatory responses in the lesions. The activity of these potent effector T cells is therefore carefully controlled to prevent unwanted tissue injury under physiological conditions. A complex interplay of stop and go signals to the skin-resident T cells provides a delicate balance between cell death and survival, thereby determining the degree and outcome of inflammation generated in response to pathogens or antigens. This consideration may provide important insights into the way in which skin-resident T cells maintain immunological homeostasis in the skin.Current Opinion in Allergy and Clinical Immunology 09/2002; 2(4):317-23. · 3.40 Impact Factor
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ABSTRACT: NKT cells express both NK cell-associated markers and TCR. Classically, these NK1.1+TCRalphabeta+ cells have been described as being either CD4+CD8- or CD4-CD8-. Most NKT cells interact with the nonclassical MHC class I molecule CD1 through a largely invariant Valpha14-Jalpha281 TCR chain in conjunction with either a Vbeta2, -7, or -8 TCR chain. In the present study, we describe the presence of significant numbers of NK1.1+TCRalphabeta+ cells within lymphokine-activated killer cell cultures from wild-type C57BL/6, CD1d1-/-, and Jalpha281-/- mice that lack classical NKT cells. Unlike classical NKT cells, 50-60% of these NK1.1+TCRalphabeta+ cells express CD8 and have a diverse TCR Vbeta repertoire. Purified NK1.1-CD8alpha+ T cells from the spleens of B6 mice, upon stimulation with IL-2, IL-4, or IL-15 in vitro, rapidly acquire surface expression of NK1.1. Many NK1.1+CD8+ T cells had also acquired expression of Ly-49 receptors and other NK cell-associated molecules. The acquisition of NK1.1 expression on CD8+ T cells was a particular property of the IL-2Rbeta+ subpopulation of the CD8+ T cells. Efficient NK1.1 expression on CD8+ T cells required Lck but not Fyn. The induction of NK1.1 on CD8+ T cells was not just an in vitro phenomenon as we observed a 5-fold increase of NK1.1+CD8+ T cells in the lungs of influenza virus-infected mice. These data suggest that CD8+ T cells can acquire NK1.1 and other NK cell-associated molecules upon appropriate stimulation in vitro and in vivo.The Journal of Immunology 11/2000; 165(7):3673-9. · 5.52 Impact Factor