Angelina M. Bilate

Induced CD4+Foxp3+ Regulatory T Cells in Immune Tolerance

Regulatory T lymphocytes are essential to maintain homeostasis of the immune system, limiting the magnitude of effector responses and allowing the establishment of immunological tolerance. Two main types of regulatory T cells have been identified--natural and induced (or adaptive)-and both play significant roles in tuning down effector immune responses. Adaptive CD4(+)Foxp3(+) regulatory T (iTreg) cells develop outside the thymus under a variety of conditions. These include not only antigen presentation under subimmunogenic or noninflammatory conditions, but also chronic inflammation and infections. We speculate that the different origin of iTreg cells (noninflammatory versus inflammatory) results in distinct properties, including their stability. iTreg cells are also generated during homeostasis of the gut and in cancer, although some cancers also favor expansion of natural regulatory T (nTreg) cells. Here we review how iTreg cells develop and how they participate in immunological tolerance, contrasting, when possible, iTreg cells with nTreg cells.

Can TNF-α boost regulatory T cells?

Deleterious immune responses that cause autoimmune diseases such as type 1 diabetes are normally kept in check by a myriad of mechanisms. Among these, protection mediated by CD4+Foxp3+ Tregs constitutes an essential pathway. Much work over the past decade aimed to understand how Tregs affect immune responses triggered by effector T cells (Teffs), but less is known about how Teffs affect Tregs. In this issue of the JCI, Grinberg-Bleyer et al. report the clearest example thus far regarding this important aspect of Treg biology. They find that in mice, sustained protection from diabetes by Tregs is dependent on Teffs and partially dependent on TNF-α, a cytokine traditionally considered proinflammatory.

Cutting Edge: Intrathymic Differentiation of Adaptive Foxp3+ Regulatory T Cells upon Peripheral Proinflammatory Immunization

Thymocytes differentiate into CD4+ Foxp3+ regulatory T cells (TR) upon interaction between their TCR and peptide–MHC II complexes locally expressed in the thymus. Conversion of naive CD4+ T cells into TR can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3+ cells, we report de novo generation of TR upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt TR differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4+ T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for TR generation with major implications for immunity and tolerance induction.

Autoimmunity in Chagas' Disease

Chronic Chagas Disease Cardiomyopathy (CCC) is one of the few well-defined examples of human post-infectious autoimmunity, as documented by several groups in over 50 publications. The time scale dissociation between primary infection with high tissue and blood parasitism and tissue pathology, allied to the scarcity of T. cruzi in CCC heart lesions prompted investigators as early as 70 years ago to suggest that the mononuclear cell infiltrate should directly damage the heart in an autoimmune fashion. This chapter discusses evidence for autoimmunity as a major factor for heart tissue damage in CCC. Unraveling the mechanism by which an infectious agent can trigger organ-specific autoimmunity may lead to reverse strategies for identifying putative triggering infectious agents in autoimmune diseases of suspected infectious etiology. In addition, testing current concepts on molecular pathogenesis of human autoimmune disorders on proven post-infectious autoimmune disease like CCC and rheumatic fever may allow the early identification of susceptible individuals and therapy of affected patients.

Expression of inflammatory mediators and differential progression of acute myocarditis and chronic experimental chagasic cardiomyopathy in Syrian hamsters infected with Trypanosoma cruzi

Chagas’ disease, caused by protozoan Trypanosoma cruzi, is a significant cause of mortality and morbidity in many Latin-American countries, where it is estimated that 13 million people may be infected. Previous results from our group show that, with a single combination of parasite (Strain Y) and genetically heterogeneous host (Syrian hamster), it is possible to reproduce the range of different outcomes of human Chagas’ disease. In the present study, we tested the hypothesis that the inflammatory infiltrate and its locally produced mediators may be related to morbidity and mortality in the acute phase and with the severity of chronic cardiomyopathy in the Syrian hamster model of T. cruzi infection using Strain Y. Like humans, hamsters infected by T. cruzi Strain Y show different patterns of evolution in both the acute and chronic phases. In the acute phase, 30-50% of animals showed symptoms such as cachexia, lethargy, vomiting, and diarrhea, which were related with mortality during this stage. The presence of circulating parasites on the 13th day post-infection (PI) was associated with intense cardiac parasitism on the date spontaneous death during the acute phase. High cardiac parasitism, in addition to its association with symptoms, was also associated with high expression of mRNA for IL-10, TNF-α, and genes activated by inflammatory cytokines (A20 and iNOS) in the myocardium. During the acute phase, blockade of TNF-α with Etanercept lead to increased parasitism in blood and heart and to increased expression of IL-10 in the myocardium of asymptomatic animals. In the chronic phase of infection, although the intensity of myocarditis was positively correlated with macroscopic dilation of the left ventricle, none of these variables were associated with death during the chronic phase. In this phase, there was a predominance of expression of mRNA for IFN-γ in the myocardium over that of TNF-α and IL-10, although the latter two were also detected at increased levels. Death during the chronic phase was associated only with the expression of A20. In the chronic phase, treatment with Etanercept worsened post-T. cruzi infection chronic cardiomyopathy, as measured by ventricular dysfunction and left ventricle dilation, and lead to increased expression of IL-10 and decreased expression of iNOS mRNAs in the myocardium. Overall, cardiac parasitism in the acute phase seems to determine the levels of expression of cytokines such as TNF-α and IFN-γ and genes activated by TNF-α and IFN-γ such as iNOS. The low parasitism and cytokines in the myocardium of asymptomatic animals suggests that these animals were able to control parasitism before its dissemination to the tissues during the acute phase. In the chronic phase, although significant levels of cytokines were present in the myocardium and the intensity local inflammation is involved in the progression of Chagas disease cardiomyopathy to the dilated form, these factors seem not to be determinants of mortality in chronically infected animals. This indicates that inflammatory mechanisms play an important pathogenic role in the evolution of T. cruzi chronic cardiomyopathy, but are not sufficient to lead to death.