Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Salvador Iborra; María Martínez-López; Francisco J. Cueto; Ruth Conde-Garrosa; Carlos Del Fresno; Helena M. Izquierdo; Clare L. Abram; Daiki Mori; Yolanda Campos-Martín; Rosa María Reguera; Benjamin Kemp; Sho Yamasaki; Matthew J. Robinson; Manuel Soto; Clifford A. Lowell; David Sancho

doi:10.1016/j.immuni.2016.09.012

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Salvador Iborra, María Martínez-López, Francisco J. Cueto, Ruth Conde-Garrosa, Carlos Del Fresno, Helena M. Izquierdo, Clare L. Abram, Daiki Mori, Yolanda Campos-Martín, Rosa María Reguera, Benjamin Kemp, Sho Yamasaki, Matthew J. Robinson, Manuel Soto, Clifford A. Lowell, David Sancho

Research output: Contribution to journal › Article › peer-review

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Abstract

C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c⁺ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

Original language	English
Pages (from-to)	788-801
Number of pages	14
Journal	Immunity
Volume	45
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2016.09.012
Publication status	Published - Oct 18 2016

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2016.09.012

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Iborra, S., Martínez-López, M., Cueto, F. J., Conde-Garrosa, R., Del Fresno, C., Izquierdo, H. M., Abram, C. L., Mori, D., Campos-Martín, Y., Reguera, R. M., Kemp, B., Yamasaki, S., Robinson, M. J., Soto, M., Lowell, C. A., & Sancho, D. (2016). Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection. Immunity, 45(4), 788-801. https://doi.org/10.1016/j.immuni.2016.09.012

Iborra, S, Martínez-López, M, Cueto, FJ, Conde-Garrosa, R, Del Fresno, C, Izquierdo, HM, Abram, CL, Mori, D, Campos-Martín, Y, Reguera, RM, Kemp, B, Yamasaki, S, Robinson, MJ, Soto, M, Lowell, CA & Sancho, D 2016, 'Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection', Immunity, vol. 45, no. 4, pp. 788-801. https://doi.org/10.1016/j.immuni.2016.09.012

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title = "Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection",

abstract = "C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.",

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AU - Iborra, Salvador

AU - Martínez-López, María

AU - Cueto, Francisco J.

AU - Conde-Garrosa, Ruth

AU - Del Fresno, Carlos

AU - Izquierdo, Helena M.

AU - Abram, Clare L.

AU - Mori, Daiki

AU - Campos-Martín, Yolanda

AU - Reguera, Rosa María

AU - Kemp, Benjamin

AU - Yamasaki, Sho

AU - Robinson, Matthew J.

AU - Soto, Manuel

AU - Lowell, Clifford A.

AU - Sancho, David

PY - 2016/10/18

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N2 - C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

AB - C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration, and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

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Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Abstract

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