IL-15 is a growth factor and an activator of CD8 memory T cells.
Weng Nan-Ping,Liu Kebin,Catalfamo Marta,Li Yu,Henkart Pierre A
Annals of the New York Academy of Sciences
Memory lymphocytes, arising from naïve lymphocytes after antigenic stimulation and being long-lived, are the cellular basis for immunological memory. Recent studies of CD8 T cells suggest that generation of CD8 memory T cells requires the engagement of T cell antigen receptors (TCR) with antigen, yet the maintenance of CD8 memory T cells appears to be dependent on cytokines, such as IL-15, independent of TCR. Although considerable progress has been made in understanding the molecular and cellular events of TCR-induced differentiation and proliferation in the past decade, less is known about the mechanisms of IL-15 action. From a kinetic and comparative analysis of the responses of memory phenotype CD8 T cells to IL-15 and TCR stimulation in vitro, we found that IL-15 and anti-CD3 induce highly similar responses in memory phenotype CD8 T cells as measured by general gene expression profiles, synthesis of effector molecules (IFNgamma, TNFbeta, granzyme B and perforin), induction of cytotoxicity, and cellular proliferation. These findings indicate that IL-15 is not only a growth factor but also an antigen-independent activator for CD8 memory T cells.
IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells.
Dubois Sigrid,Mariner Jennifer,Waldmann Thomas A,Tagaya Yutaka
We report intriguing aspects of the contribution of IL-15Ralpha to IL-15 functions. Consistent with high-affinity interactions between IL-15 and IL-15Ralpha, these two molecules form stable complexes on the cell surface of activated monocytes. The formation of IL-15/IL-15Ralpha complexes on cell surfaces induces a trans-endosomal recycling of IL-15 leading to the persistence of surface-bound IL-15 due to the constant reappearance of IL-15 on plasma membranes. This complex contributes to the long survival of T cells expressing IL-15Ralpha after IL-15 withdrawal. Finally, these complexes on activated monocytes present IL-15 in trans to target cells such as CD8(+) T cells that express only IL-2/15Rbeta and gammac upon cell-cell interaction.
Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma.
Adachi Takeya,Kobayashi Tetsuro,Sugihara Eiji,Yamada Taketo,Ikuta Koichi,Pittaluga Stefania,Saya Hideyuki,Amagai Masayuki,Nagao Keisuke
The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) TRM cells, and IL-7 for CD8(+) and CD4(+) TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) TRM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.
Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8 T cells activation via JAK-STAT pathway in vitiligo.
Chen Xuguang,Guo Weinan,Chang Yuqian,Chen Jiaxi,Kang Pan,Yi Xiuli,Cui Tingting,Guo Sen,Xiao Qian,Jian Zhe,Li Kai,Gao Tianwen,Li Shuli,Liu Ling,Li Chunying
Free radical biology & medicine
Oxidative stress and effector memory CD8 T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8 T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal HO content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans-presentation by activating NF-κB signaling in keratinocytes. What's more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8 T activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8 T activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to the activation of CD8 T, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.