Skin-derived interleukin-7 contributes to the proliferation of lymphocytes in cutaneous T-cell lymphoma

Abstract

Cutaneous T-cell lymphomas (CTCLs) are malignancies of T cells that have a special affinity for the skin. We have previously reported that much of the T-cell receptor repertoire is altered in CTCL, and both malignant and nonmalignant clones are numerically expanded, presumably in response to T-cell trophic cytokines. We therefore examined levels of the T-cell trophic cytokines IL-2, IL-4, IL-7, IL-12, IL-13, and IL-15 in plasma in 93 CTCL patients and healthy controls. Only IL-7 levels were elevated in CTCL. We next looked at lesional skin from patients with CTCL and found elevated levels of IL-7 mRNA. Explant cultures of normal and lesional CTCL skin biopsies revealed significantly more IL-7 protein production in CTCL skin. Additionally, cultures of CTCL skin released greater numbers of T cells than normal skin; this was blocked by the addition of an IL-7 neutralizing antibody. Finally, these cultures induced proliferation of normal peripheral skinhoming T cells that were added to the cultures. These observations led us to postulate that IL-7 produced by skin cells contributes to the survival and proliferation of T cells within skin lesions and is likely the source of elevated circulating IL-7 in CTCL. IntroductionCutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders of the skin 1 and are regarded as a subset of extranodal non-Hodgkin T-cell lymphomas of skinhoming memory T cells. 2 Among CTCL patients with peripheral blood involvement, there are greater numbers of T cells expressing the skin-homing cutaneous lymphocyte antigen (CLA) and the chemokine receptor CCR4 than are present in healthy donors. 3 Furthermore, the CCR4 ligand CCL17 is highly expressed on the endothelial cells in CTCL skin lesions. 3 These findings, together with the increased expression of E selectin and ICAM-1 in CTCL lesions, 4,5 suggest that the appropriate microenvironment exists for the entry of skin-homing T cells into CTCL lesions. 3 These malignant T cells may be found singly or collectively within the epidermis and admixed with an infiltrate of mononuclear cells within the papillary dermis underlying the involved epidermis.We recently reported that in all cases of advanced CTCL, and many cases of early disease, there is a significant disruption of the diversity of the T-cell repertoire in peripheral blood. 6 T-cell receptor beta-variable (BV) spectratyping revealed diminished complexity in many BV families, 6 and this correlated with diminished T-cell receptor excision circle (TREC) levels. 7 Both observations are consistent with the idea that some normal T cells are being removed from circulation and other T cells are proliferating to fill the space that this removal creates in the T-cell compartment. The idea that there may be a proliferative stimulus in the peripheral blood of CTCL patients led us to examine peripheral blood plasma for the presence of T-cell trophic cytokines Patients and healthy controls were studied, and plasma levels of interleukin-2 (IL-2), IL-4, IL-7, IL-12, IL-13, ...

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…In line with the results from STATs, resulting in malignant cell proliferation and survival. [23][24][25] In advanced disease, malignant T cells display a cytokine-independent, constitutive activation of JAK3, which drives a constitutive activation of STAT3 that, in turn, increases survival and resistance to apoptosis in malignant T cells, 26,27 and induces production of cytokines involved in eosinophilia and erythroderma (IL-5), as well as T helper 2 (Th2), 28 and Th17 29 cytokines. Furthermore, the pathway is believed to play a role in creating a pro-oncogenic inflammatory environment via production of VEGF 30 and IL-10 31 and induction of suppressor of cytokine signaling-3 (SOCS-3), 32 which confers resistance to IFNα in malignant T cells.…”

Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques

“…[35][36][37] Moreover, most of the molecules that were induced after IL-7 treatment were described as participating in T-cell homing into these organs during inflammatory reactions. [38][39][40][41][42] The expression patterns of chemokines/chemokine receptors suggest that naive and memory CD4 ϩ T cells are directed to the gut through CCR6/CCL20 and/or CCR9/CCL25 expression, whereas all T-cell subsets (but the TEM CD8 ϩ , which barely express CCR7) might migrate into the skin and the lungs where CCR7-ligands (CCL19, CCL21) expression is increased. The involvement of IL-7-driven T-cell homing into nonlymphoid tissues in innate and adaptive immunity remains to be clarified, but it is possible that the injection of R-sIL-7gly mimicked certain aspects of antigen-induced immune activa- …”

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

“…19,34,35 Indeed, as disease progresses, neoplastic CD4 1 T cells express higher levels of IL-15. 19 Furthermore, IL-15 overexpression alone can induce CTCL in a murine model of the disease.…”