Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1-Dependent Mechanisms.
Galectin-1 (Gal-1), an endogenous glycan-binding protein, is widely distributed at sites of inflammation and microbial invasion. Despite considerable progress regarding the immunoregulatory activity of this lectin, the role of endogenous Gal-1 during acute parasite infections is uncertain. In this study, we show that Gal-1 functions as a negative regulator to limit host-protective immunity following intradermal infection with Trypanosoma cruzi. Concomitant with the upregulation of immune inhibitory mediators, including IL-10, TGF-β1, IDO, and programmed death ligand 2, T. cruzi infection induced an early increase of Gal-1 expression in vivo. Compared to their wild-type (WT) counterpart, Gal-1-deficient (Lgals1(-/-)) mice exhibited reduced mortality and lower parasite load in muscle tissue. Resistance of Lgals1(-/-) mice to T. cruzi infection was associated with a failure in the activation of Gal-1-driven tolerogenic circuits, otherwise orchestrated by WT dendritic cells, leading to secondary dysfunction in the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells. This effect was accompanied by an increased number of CD8(+) T cells and higher frequency of IFN-γ-producing CD4(+) T cells in muscle tissues and draining lymph nodes as well as reduced parasite burden in heart and hindlimb skeletal muscle. Moreover, dendritic cells lacking Gal-1 interrupted the Gal-1-mediated tolerogenic circuit and reinforced T cell-dependent anti-parasite immunity when adoptively transferred into WT mice. Thus, endogenous Gal-1 may influence T. cruzi infection by fueling tolerogenic circuits that hinder anti-parasite immunity.
Instituto de Investigaciones en Microbiología y Parasitología Médicas, Facultad de Medicina, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, C1121 Buenos Aires, Argentina; cvponcini@gmail.com.
Carolina V
CV
Poncini
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428 Buenos Aires, Argentina; Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands; and.
Juan M
JM
Ilarregui
Instituto de Investigaciones en Microbiología y Parasitología Médicas, Facultad de Medicina, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, C1121 Buenos Aires, Argentina;
Estela I
EI
Batalla
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands; and.
Steef
S
Engels
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428 Buenos Aires, Argentina;
Juan P
JP
Cerliani
Instituto de Investigaciones en Microbiología y Parasitología Médicas, Facultad de Medicina, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, C1121 Buenos Aires, Argentina;
Marcela A
MA
Cucher
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands; and.
Yvette
Y
van Kooyk
Instituto de Investigaciones en Microbiología y Parasitología Médicas, Facultad de Medicina, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, C1121 Buenos Aires, Argentina;
Stella M
SM
González-Cappa
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428 Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428 Buenos Aires, Argentina.
Gabriel A
GA
Rabinovich
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology* / Q000401:mortality / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology*; D037483:Galectin 1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D059208:Parasite Load; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014349:Trypanosoma cruzi / Q000276:immunology*
D037483:Galectin 1; C583637:IDO1 protein, mouse; C556062:IL10 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007371:Interferon-gamma