RESUMO
Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG(-/-) mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on type I IFNs. The stimulator of IFN genes pathway was discovered to be a potent inducer of sIL-15 complexes and was required for optimal production of sIL-15 complexes in response to Ab-mediated T cell depletion and TBI, suggesting products of cell death drive production of sIL-15 complexes after lymphodepletion. Lastly, we provide evidence that IL-15 induced by inflammatory signals in response to lymphodepletion drives lymphocyte responses, as memory CD8 T cells proliferated in an IL-15-dependent manner. Overall, these studies demonstrate that the form in which IL-15 is expressed, its kinetics and cellular sources, and the inflammatory signals involved are differentially dictated by the manner in which lymphopenia is induced.
Assuntos
Interleucina-15/imunologia , Depleção Linfocítica , Linfopenia/imunologia , Animais , Modelos Animais de Doenças , Inflamação/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVE: To evaluate an observational-behavioral pain tool among individuals with acute poststroke aphasia. METHODS: We performed a randomized, double-blind, controlled study of experimental pain assessment among 36 adult patients with acute poststroke aphasia. Patients were administered 3 levels of mechanical pain, including placebo. The behavioral responses were video recorded and then evaluated by 3 neurology nurses using the Pain Assessment Checklist for Seniors With Limited Ability to Communicate (PACSLAC-II). Pain-specific facial action units were quantified with FaceReader version 6.1. RESULTS: Median PACSLAC-II ratings for 0-, 2-, and 4.5-lb weight stimuli were 2 (0, 3), 1 (0, 3), and 2 (1, 5), respectively. Overall, differences were not detected (p = 0.06). Pairwise comparisons with the Wilcoxon method demonstrated significance in differentiating PACSLAC-II ratings of patients experiencing the 4.5-lb stimulus vs either the 2-lb weight (p = 0.03) or placebo (p = 0.05). Overall interrater reliability by the Cronbach α was strong at 0.87, 0.94, and 0.96 for weights of 0, 2, and 4.5 lb, respectively. Pain-specific facial activation and negative valence were observed similarly in placebo and experimental pain groups. CONCLUSIONS: Among our cohort with acute poststroke aphasia, the PACSLAC-II was not able to overall differentiate patients experiencing experimental mechanical pain, although differences in those experiencing the strongest pain stimulus were significant. The detection of pain-specific facial activation and negative valence in the placebo group indicates that pain and distress are unmet needs among stroke patients who are unable to verbally communicate.
Assuntos
Afasia/complicações , Medição da Dor/métodos , Dor/diagnóstico , Dor/etiologia , Idoso , Afasia/etiologia , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Física/efeitos adversos , Estimulação Física/métodos , Psicofísica , Autorrelato , Acidente Vascular Cerebral/complicaçõesRESUMO
Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity.