Unconventional Pro-inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi.

Melisa Gorosito Serrán,Carola G Vinuesa,Adriana Gruppi,Facundo Fiocca Vernengo,María C Ramello,Cristian G Beccaría,Eva V Acosta Rodriguez,Daniela A Bermejo,Carolina L Montes,Amelia G Cook,Jimena Tosello Boari

doi:10.3389/fimmu.2017.01548

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice) infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNγ+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44− cells, which is commonly associated with a naïve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able to regulate TNF-producing CD4+ T cells since their absence favor the increase of the number of TNF+ CD4+ in T. cruzi-infected mice.

Highlights

Chagas’ disease is caused by the intracellular protozoan parasite Trypanosoma cruzi
To deeply evaluate the disease progression and T cell response during T. cruzi infection in mice deficient in mature B cells, WT and muMT mice were infected with Y strain trypomastigotes of T. cruzi
As previously reported [28, 31], muMT mice were more susceptible than WT mice to T. cruzi infection, as most of them succumbed after 20 days post infection (Dpi) (Figure 1A)

Summary

Introduction

Chagas’ disease is caused by the intracellular protozoan parasite Trypanosoma cruzi This acute and chronic illness affects millions of people in the Americas [1] and show increasing frequency in non-endemic areas in Europe and North America due to human migration [2]. During experimental T. cruzi infection, the innate and acquired cell-mediated immune responses, involving many cell populations such as NK cells, CD4+, and CD8+ T cells, are required for host resistance [3]. These protective responses are mainly mediated by cytokines such as TNF and IFNγ, which activate macrophages to destroy ingested parasites and to release pro-inflammatory cytokines [4,5,6,7,8]. The inflammatory response must be properly balanced; it has to be strong enough to control the pathogen but tightly controlled to minimize immune-mediated pathology [17, 18]

Methods

Results

Conclusion