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      Administration of a nondepleting anti-CD25 monoclonal antibody reduces disease severity in mice infected with Trypanosoma cruzi

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          Abstract

          The role of CD25+ regulatory T cells during the course of Trypanosoma cruzi infection has been previously analyzed, and the bulk of results have shown a limited role for this T cell subpopulation. In this study, we have used an IgM, nondepleting monoclonal antibody (mAb) aiming at blocking interleukin (IL)-2 activity on CD25+ T cells. The administration of this antibody 10 days before infection increased the resistance of outbred Swiss mice to the Colombian strain of T. cruzi. Anti-CD25-treated mice had lower parasitemia and augmented numbers of effector memory T cells. In addition, these animals showed higher numbers of splenic T cells secreting IFN-γ and TNF-α, both cytokines described to be involved in the resistance to T. cruzi infection. The same treatment also increased the numbers of splenic T cells that produced homeostatic and regulatory cytokines, such as IL-2 and IL-10, and CD4+CD25+ T cells. The administration of nondepleting anti-CD25 mAb at the beginning of the chronic phase, when parasites were cleared from the blood, halted the inflammatory process in the heart, without any signs of infection reactivation. These results indicate that nondepleting anti-CD25 monoclonal antibodies may be useful to treat chronic Chagas’ disease.

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          Most cited references 35

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          A function for interleukin 2 in Foxp3-expressing regulatory T cells.

          Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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            In vivo switch to IL-10–secreting T regulatory cells in high dose allergen exposure

            High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell–related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen–specific Th1 and Th2 cells show a switch toward interleukin (IL) 10–secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte–associated antigen 4 and programmed death 1 play roles in allergen-specific T cell suppression. In contrast to its role in mucosal allergen tolerance, transforming growth factor β does not seem to be an essential player in skin-related allergen tolerance. Thus, rapid switch and expansion of IL-10–producing Tr1 cells and the use of multiple suppressive factors represent essential mechanisms in immune tolerance to a high dose of allergens in nonallergic individuals.
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              Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells.

              In this study we demonstrate a new form of immunoregulation: engagement on CD4(+) T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (T(H)1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4(+) T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4(+) T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-gamma (IFN-gamma). Finally, gammadelta T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 June 2014
                : 4
                : 2
                : 128-137
                Affiliations
                [ 1 ] Gonçalo Moniz Research Centre, Fiocruz, Salvador, Bahia, Brazil
                [ 2 ] Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Rio de Janeiro, Brazil
                [ 3 ] Laboratory 36L, Faculty of Medicine of Petropolis-FMP/FASE, Av. Barao do Rio Branco, 1003, 25.680-120, Centro, Petropolis, Rio de Janeiro, Brazil
                [ 4 ] Faculty of Nursing and Obstetrics, Juárez University of Durango State, Avenida Cuauhtémoc 223, 34000, Durango, Mexico
                [ 5 ] Institute for Microbiology and Hygiene, Campus Benjamin Franklin, Charité Medical School, Hindenburgdamm 27, D-12203, Berlin, Germany
                Author notes

                These authors contributed equally to the work.

                Article
                6
                10.1556/EuJMI.4.2014.2.6
                4029292
                24883199
                Categories
                Original Article

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