title: IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease.
abstract: Reactive oxygen and nitrogen species are important microbicidal agents and are also involved in lymphocyte unresponsiveness during experimental infections. Many of the biological effects attributed to nitric oxide are mediated by peroxynitrites, which induce the nitration of immune cells, among others. Our group has demonstrated that nitric oxide is involved in the suppressive activity of myeloid-derived suppressor cells inTrypanosoma cruzi-infected mice, with a higher number of CD8+ T cells suffering surface-nitration compared to uninfected controls. Studying the functional and phenotypic features of peripheral CD8+ T cells from chagasic patients and human cells experimentally infected withT. cruzi, we found that different regulatory mechanisms impaired the effector functions of T cytotoxic population from seropositive patients. Peripheral leukocytes from chagasic patients showed increased nitric oxide production concomitant with increased tyrosine nitration of CD8+ T cells. Additionally, this cytotoxic population exhibited increased apoptotic rate, loss of the TCRζ-chain, and lower levels of CD107a, a marker of degranulation. Strikingly, IL-6 stimulation ofin vitro-infected peripheral blood mononuclear cells obtained from healthy donors, bluntedT. cruzi-induced nitration of CD3+CD8+ cells, and increased their survival. Furthermore, the treatment of these cultures with an IL-6 neutralizing antibody increased the percentage ofT. cruzi-induced CD8+ T cell nitration and raised the release of nitric oxide. The results suggest that the under-responsiveness of cytotoxic T cell population observed in the setting of long-term constant activation of the immune system could be reverted by the pleiotropic actions of IL-6, since this cytokine improves its survival and effector functions.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Liliana Maria
authors.initials: LM
authors.lastname: Sanmarco
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo , Córdoba , Argentina.
authors.forename: Laura Marina
authors.initials: LM
authors.lastname: Visconti
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Eberhardt
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Ramello
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Nicolás Eric
authors.initials: NE
authors.lastname: Ponce
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo , Córdoba , Argentina.
authors.forename: Natalia Beatriz
authors.initials: NB
authors.lastname: Spitale
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo , Córdoba , Argentina.
authors.forename: Maria Lola
authors.initials: ML
authors.lastname: Vozza
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo , Córdoba , Argentina.
authors.forename: Germán Andrés
authors.initials: GA
authors.lastname: Bernardi
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Susana
authors.initials: S
authors.lastname: Gea
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo , Córdoba , Argentina.
authors.forename: Angel Ramón
authors.initials: AR
authors.lastname: Minguez
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , Córdoba , Argentina.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Aoki
keywords: CD39; CD73; Trypanosoma cruzi infection; oxidative stress; peroxynitrite; tyrosine nitration