Regulatory and Stimulatory Functions of IL-10 During Experimental Trypanosoma Cruzi Infection

Event Abstract Back to Event Regulatory and stimulatory functions of IL-10 during experimental Trypanosoma cruzi infection Agustina M. Pino-Martinez1, Cristian G. Miranda1, Estela I. Batalla1, Maria E. Solana1, Silvia A. Repetto1, Stella M. Gonzalez Cappa1 and Catalina D. Alba Soto1* 1 Facultad de Medicina, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), UBA-CONICET, Argentina, Argentina IL-10 is a cytokine involved in the regulation of the inflammatory response. Several preclinical studies suggest that strategies timely adjusted to inhibit or enhance its production could be effective to achieve pathogen control or to prevent tissue damage by inflammation in the context of infectious diseases. Regarding individuals chronically infected with the protozoan parasite Trypanosoma cruzi, this cytokine appears to have an important role in delaying the onset of cardiac Chagas´ disease cardiomyopathy. In a recent report, the cytokine profile of a cohort of chronically infected individuals revealed that a low IL-10 serum level was the most prominent signature of a switch from the anti-inflammatory profile of asymptomatic patients to a proinflammatory one of patients with cardiac symptoms. In response to infection with T. cruzi IL-10 is produced by different cell types. Our previous works demonstrated that IL-10 is involved in different immunoregulatory mechanisms elicited in response to experimental murine Chagas disease. We evaluated the effect of the global absence of IL-10 on the immune response to experimental T. cruzi infection of mice deficient in IL-10 from Balb-c background (IL-10 KO). We found that the lack of IL-10 does not confer increased resistance to T. cruzi infection with parasite strains of high and low virulence that produce lethal or sublethal infections respectively. Indeed, we observed higher parasitemia levels, parasite load in tissues, weight loss and morbidity in mice deficient in IL-10 compared to their wild type counterparts. This result seemed paradoxical in view of the well described immunoregulatory properties of IL-10 and the relevance of Th1 and Tc1 lymphocytes in controlling a protozoan with intracellular multiplication in the mammalian host such as T. cruzi. To understand the increased susceptibility of T. cruzi infected IL-10 KO mice, we evaluated the main effector mechanisms involved in parasite control. We observed that, in the absence of IL-10, serum levels of IFN-γ increased almost 9 times in infected mice. Peritoneal macrophages from T.cruzi infected IL-10 KO mice displayed a significantly higher ability to produce nitric oxide than controls. Regarding professional antigen presenting cells as dendritic cells, macrophages and B lymphocytes, their surface expression of MHC II and costimulatory molecules (CD86 and CD80) did not differ significantly between infected wild type (WT) and IL-10 KO mice. Then, we studied the frequency of T cells in spleen and peripheral blood during the acute T. cruzi infection. IL-10 KO infected mice showed no expansion of the splenic or circulating CD8+ T cell pool a characteristic feature of the acute phase infection. As for CD4+ T cell population, their kinetics did not differ significantly between IL-10KO or WT mice. Consequently, the CD4+/CD8+ T cell ratio was significantly altered in IL-10 KO mice. We explored ex vivo the effector function of CD8+ T cells. CD8+ T cells from mouse IL-10 KO infected mice exhibited lower cytotoxic potential (surface expression of CD107a +) and lower production of IFN-γ than infected WT counterparts in response to a non-specific stimulus. Furthermore, the relative and absolute number of splenic apoptotic (Annexin V binding) CD8+ T cells was enhanced in infected IL-10 KO mice. CD8+ T cells are the main cell population that participates in the control of intracellular parasites throughthe destruction of T. cruziinfected cells. Thus, weanalyzed theirfrequency in cardiac infiltrates of infectedmice. Twenty-one days after infection,CD8+ T cells are the major cellular component of the infiltrates from WT infected mice with a clear correlation with the expansion of this cell population in secondary lymphoid organs. In the absence of IL-10, fewer number of CD8+ T cells accumulate in cardiac tissue infiltrates. At the chronic stage of infection (5 months post-infection), the extension and number of infiltrates decreased globally but IL-10 still appeared to be necessary to drive the accumulation of CD8+ T cells in these tissues. We also evaluated, in our experimental model of T. cruzi infection, the participation of IL-10 in the induction of target tissue damage in a comparative histopathological study of heart, and quadriceps of IL-10 KO and WT mice at acute (21 dpi.) and chronic (8 mpi) infection. These studies confirmed that IL-10 participates in the control of tissue inflammation and to prevent permanent damage to the muscle fibers (calcification, fibrosis, fatty replacement). Taken together, our results indicate that the absence of IL-10 does not contribute to increased pathogen removal although this cytokine appears to be necessary to control tissue inflammation at the acute and chronic infection. Surprisingly, our experimental model also revealed that IL-10 plays a central role in the expansion, survival and functional activation of CD8+ T cells, the most relevant lymphocyte population for parasite control in host tissues both at acute and chronic stages of infection. The expansion, activation and contraction dynamics of CD8+ T cells has large consequences on the induction of memory and intracellular pathogen control. It is therefore relevant to study the role of these cytokines on both differentiation and maintenance of CD8+ T cells. In conclusion, IL-10 plays a previously unrecognized immunostimulatory role on CD8+ T cells during acute infection with T. cruzi. Still, through their immunoregulatory functions, IL-10 appears to limit tissue damage caused by inflammation that occurs in response to pathogen invasion. Acknowledgements This work received support from UBACYT, CONICET and FONCYT. Keywords: Trypanosoma cruzi, IL-10, IL-10 deficient mice, Experimental Chagas´disease, CD8+ T cells, immunopathology Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Infectious and parasitic diseases Citation: Pino-Martinez AM, Miranda CG, Batalla EI, Solana ME, Repetto SA, Gonzalez Cappa SM and Alba Soto CD (2015). Regulatory and stimulatory functions of IL-10 during experimental Trypanosoma cruzi infection. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00190 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 13 May 2015; Published Online: 14 Sep 2015. * Correspondence: Dr. Catalina D Alba Soto, Facultad de Medicina, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), UBA-CONICET, Argentina, Ciudad Autónoma de Buenos Aires, CP1121, Argentina, catalina.alba@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Agustina M Pino-Martinez Cristian G Miranda Estela I Batalla Maria E Solana Silvia A Repetto Stella M Gonzalez Cappa Catalina D Alba Soto Google Agustina M Pino-Martinez Cristian G Miranda Estela I Batalla Maria E Solana Silvia A Repetto Stella M Gonzalez Cappa Catalina D Alba Soto Google Scholar Agustina M Pino-Martinez Cristian G Miranda Estela I Batalla Maria E Solana Silvia A Repetto Stella M Gonzalez Cappa Catalina D Alba Soto PubMed Agustina M Pino-Martinez Cristian G Miranda Estela I Batalla Maria E Solana Silvia A Repetto Stella M Gonzalez Cappa Catalina D Alba Soto Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.