IMPAM   23988
INSTITUTO DE INVESTIGACIONES EN MICROBIOLOGIA Y PARASITOLOGIA MEDICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
A role for IL-10 in the expansion and functional activation of CD8+ T cells during acute Trypanosoma cruzi infection
Autor/es:
PINO-MARTÍNEZ, AGUSTINA M.; REPETTO, SILVIA ANALIA; MIRANDA, CRISTIAN G.; GONZALEZ-CAPPA , STELLA MARIS; BATALLA, ESTELA I.; ALBA SOTO, CATALINA D.
Lugar:
Cancún
Reunión:
Congreso; Immuno Mexico 2018, XII Congress of the Latin American Association of Immunology and XXIII Congress of the Mexican Society of Immunology; 2018
Institución organizadora:
Mexican Society of Immunology
Resumen:
A role for IL-10 in the expansion and functional activation of CD8+ T cells during acute Trypanosoma cruzi infectionAgustina M. Pino Martinez1, 2, Cristian G. Miranda1, 2, Estela I. Batalla1, 2, Stella M. González Cappa1, 2 and Catalina D. Alba Soto1, 2*1Departamento de Microbiología, Parasitología e Inmunología., Facultad de Medicina, Universidad de Buenos Aires, Argentina2Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM)., Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), ArgentinaChagas disease is a potentially life-threatening illness caused by the intracellular protozoan parasite Trypanosoma cruzi (T. cruzi). Among T. cruzi chronically-infected individuals, 35% will develop mild- to severe cardiac and less frequently digestive forms of the disease and the rest of them will show no signs or symptoms of illness. It is currently estimated that 6-7 million people are infected with the addition of 56,000 new cases per year and 12,000 deaths. Yet, the migratory waves between Latin America and wealthy countries have spread the disease to North America, Europe, and the Western Pacific. According to WHO estimations for 2011, 300,000 T. cruzi infected people resided in the United States, 90,000 in Europe, 1,500 in Australia and 3,000 in Japan. IL-10 is a pleiotropic cytokine with immunoregulatory functions that affect diverse cell populations. Previous work from our group has demonstrated the participation of IL-10 in immunoregulatory mechanisms launched at the interphase between innate and adaptive immunity against T. cruzi ( Alba Soto CD et al. Vaccine. 2010; Poncini CV et al. Mol Immunol. 2010; Batalla EI et al. J Innate Immun. 2013; Poncini CV et al. Infect Immun. 2008). In a model of experimental infection with the protozoan T. cruzi we found augmented morbidity and lower parasite control in IL-10 deficient mice (IL-10 KO) compared to wild-type (WT) mice. To understand the increased susceptibility of T. cruzi infected IL-10 KO mice, we evaluated the performance of main effector mechanisms involved in parasite control. Despite of a Th1 balanced cytokine profile, enhanced macrophage function and dendritic cell activation IL-10 KO mice were more susceptible to infection. However, the kinetics of T cells in spleen and peripheral blood revealed that infected IL-10 KO mice failed to increase the number of spleen and circulating total CD8+ T cells, a phenomenon usually observed from the second week of infection in WT mice. Total CD8+ T cells from IL-10 KO mice exhibited diminished proliferation, cytotoxic potential, IFN-γ production and lower survival than their WT counterparts. We also studied the impact of IL-10 on the T. cruzi-specific response of CD8+ T cells. For this, we measured in vivo the cytotoxicity of CD8+ T cells that recognize an MHC-I ?restricted epitope from T. cruzi trans-sialidase, IYNVGQVSI. Lysis of target cells by parasite-specific CD8+ T cells was lower in IL-10 KO mice than in WT mice thus reflecting that the effect of IL-10 absence on CD8+ T cell function encompassed total as well as T. cruzi-specific CD8+ T cells. Moreover, the absence of IL-10 selectively affected expansion, survival and PD-1 expression of CD8+ T cells without affecting these same parameters on CD4+ T cells. CD8+ T cells from IL-10 KO infected mice exhibited a phenotype similar to that of exhausted CD8+ T cells. The participation of IL-10 in the primary expansion and functional activation of CD8+ T cells that characterizes acute in vivo infection was unexpected. In fact, the anti-inflammatory role of IL-10 has been extensively explored, while its stimulatory role has received less attention. Stimulatory properties of IL-10, including those that influence CD8+ T cells as the ones shown have been described. Accordingly, this cytokine increase their proliferation and cytotoxicity against non-specific and antigen-specific stimuli, viability during proliferation as well as the frequency of CD8+ T-cell precursors. Collectively, these findings reveal that during acute infection, IL-10 plays a previously unrecognized stimulatory role on CD8+ T cells, the most relevant lymphocyte population for the control of intracellular T. cruzi stages. Considering that the capacity to produce IL-10 can be genetically established, these results emphasize the significance of our findings for human infection. The profile of the CD8+ T cell response has a central role in the severity of human T. cruzi infection and the control of T. cruzi in sites of parasite persistence. A clear knowledge of the mechanisms that drive effector functions of this cytotoxic cell population is critical to understand factors involved in pathogen persistence and for the rational design of prophylactic strategies against T. cruzi.AcknowledgementsResearch was funded by Agencia Nacional de Promoción Científica y Tecnológica (PICT 0733-14); CONICET (PIP 2012-0913 and PIP2015-0514) and Fundación Roemmers to CDAS.