Regulated glycosylation controls the fate and function of regulatory T cells
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1
Instituto de biologia y medicina experimental, Argentina
Upon differentiation into a specific subset, CD4+ T cells undergo major changes in their glycosylation profile. We have previously demonstrated that Th1, Th17 and Th2 cells exhibit differential glycosylation patterns on their cell surface, leading to differential sensitivity to the endogenous lectin galectin-1 (Gal1). Here we investigated the impact of glycosylation in the function of T cells, focusing on regulatory T cells (Tregs). First we analyzed by mass spectometry the N-glycosylation patterns of in vitro induced Tregs (iTregs) versus in vitro non-polarized activated T cells (Teff). iTregs exhibited significantly lower levels of highly-branched complex N-glycans (p<0.05) while Teff cells showed higher levels of beta1,6 complex N-branching and free lactosamine terminals, suitable for Gal1 binding (p<0.05). Glycophenotypic analysis using a panel of plant lectins revealed that Treg cells isolated form spleens of C57Bl/6 mice exhibited high frequency of asialo-core-1 O-glycans, low levels of poly-N-acetyl-lactosamine structures and high amounts of alpha2,6-linked sialic acid (a2,6-SA) terminals, a glyco-epitope that is restrictive for Gal1 binding. Furthermore, iTregs cells presented a lower capacity (p<0.01) to bind Gal1 than Teff cells. In an in vivo model, CD4+CD25+FR4- (Foxp3-) T effector cells from mice immunized subcutaneously with OVA in Complete Freund´s Adjuvant (CFA) presented a significantly higher capacity to bind Gal1 when compared to Tregs cells (p<0,01). In a time-course study, we observed that when naive CD4+ T cells differentiate into iTregs cells, their ability to bind Gal1 decreases in a time-dependent manner as these cells increase their content of a2,6-SA. Consequently, Teff cells, but not iTregs nor natural Tregs (nTregs), were susceptible to Gal1-induced apoptosis (p<0.05). Accordingly, both iTregs and nTregs lacking the enzyme responsible of incorporating a2-6SA (St6gal1-/-) became susceptible to Gal1-induced apoptosis (p<0.05). We found that lack of a2-6 sialylation impairs Treg cell activity, as St6gal1-/- Tregs showed decreased suppressive capacity in vitro. Finally, St6gal1-/- mice immunized with myelin oligodendrocyte glycoprotein (MOG35-55) developed a more severe disease (experimental autoimmune encephalomyelitis; EAE) compared to wt mice, with higher clinical scores, higher Th1 infiltration (p<0.05), and Treg cells with lower suppressive capacity (p<0.01). Altogether, these findings highlight the critical role of sialylation in dictating the activity and fate of Treg cells.
Keywords:
regulatory T cells,
Glycosilation,
Galectin 1,
sialylation,
EAE/MS
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Poster Presentation
Topic:
Autoimmunity
Citation:
Mendez-Huergo
SP,
D'Alotto-Moreno
T,
Croci Russo
DO,
Cerliani
JP,
Marino
K,
Toscano
MA and
Rabinovich
GA
(2015). Regulated glycosylation controls the fate and function of regulatory T cells.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00204
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Received:
01 Jun 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
Mr. Santiago P Mendez-Huergo, Instituto de biologia y medicina experimental, Buenos Aires, Argentina, santiago.mendezhuergo@gmail.com