Tolerogenic signals delivered from dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving IL-27 and IL-10

ILARREGUI JM; CROCI DO; BIANCO GA; TOSCANO MA; SALATINO M; VERMEULEN ME; GEFFNER JR; RABINOVICH GA

Viña del Mar, Chile

Congreso; 9th Latin American Congress of Immunology; 2009

ALAI

&amp;amp;amp;amp;amp;amp;amp;lt;!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:Calibri; mso-ansi-language:ES; mso-fareast-language:ES;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Century; mso-fareast-font-family:Calibri; mso-hansi-font-family:Century;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --&amp;amp;amp;amp;amp;amp;amp;gt; Despite their central role in orchestrating immunity, dendritic cells (DCs) may respond to inhibitory signals by becoming tolerogenic. Here, we evaluated the impact of galectin-1, an endogenous glycan-binding protein with anti-inflammatory properties, on the physiology of DCs. Both human monocyte-derived DCs matured in the presence of LPS and galectin- 1 and murine bone marrow-derived DCs differentiated in the presence of galectin-1 (DCGal1) suppressed mixed leukocyte reactions, promoted T-cell tolerance and altered the IFN-γ, IL-17 and IL-10 secretion (p<0.05). A mechanistic analysis revealed that DCGal1 had increased activation of the JAK2-STAT3 pathway compared to control DCs. Moreover, DCGal1 had higher levels of the p28 and EBI3 subunits of IL-27, a cytokine that mediates the induction of IL-10-producing T (Tr1) cells (p<0.05). In in vivo settings, DCGal1 were not capable of protecting against challenge with B16 melanoma compared to control DCs and instead fostered a tolerogenic microenvironment at sites of tumor growth (p<0.05). Furthermore, treatment of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) with DCGal1 resulted in reduced clinical severity with lower IL-17 and IFN-γ and higher IL-10 production in wild-type, but not in IL-27 receptor-deficient α- or IL-10-deficient mice (p<0.05). Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells with broad therapeutic implications in immunopathology