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Different antibody-associated autoimmune diseases have distinct patterns of T f...

Ribeiro, Filipa; Romão, Vasco C.; Rosa, Sara; Jesus, Kátia; Agua-Doce, Ana; Barreira, Sofia; Martins, Patrícia; Silva, Susana; Nobre, Ema

Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in pa...


Route of Antigen Presentation Can Determine the Selection of Foxp3-Dependent or...

Agua-Doce, Ana; Caridade, Marta; Oliveira, Vanessa G; Bergman, Lisa; Lafaille, Maria C; Lafaille, Juan J; Demengeot, Jocelyne; Graca, Luis

It has been shown that dominant tolerance, namely in transplantation, requires Foxp3+regulatory T cells. Although most tolerance-inducing regimens rely on regulatory T cells, we found that induction of tolerance to proteins in aluminum hydroxide can be achieved in Foxp3-deficient mice using nondepleting anti-CD4 Abs. This type of tolerance is Ag specific, and tolerant mice retain immune competence to respond to...


Human blood Tfr cells are indicators of ongoing humoral activity not fully lice...

Fonseca, Valter; Agua-Doce, Ana; Maceiras, Ana Raquel; Pierson, Wim; Ribeiro, Filipa; Romão, Vasco; Pires, Ana Rita; Silva, Susana Lopes da

Germinal center (GC) responses are controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue Tfh cells has been established, the relationship between blood and tissue Tfr cells defined as CXCR5+Foxp3+T cells remains elusive. We found that blood Tfr cells are increased in Sjö...


IL-9 expression by invariant NKT cells is not imprinted during thymic development

Monteiro, Marta; Agua-Doce, Ana; Almeida, Catarina F.; Fonseca-Pereira, Diogo; Veiga-Fernandes, Henrique; Graca, Luis

Invariant NKT (iNKT) cell thymic development can lead to distinct committed effector lineages, namely NKT1, NKT2, and NKT17. However, following identification of IL-9-producing iNKT cells involved in mucosal inflammation, their development remains unaddressed. In this study, we report that although thymic iNKT cells from naive mice do not express IL-9, iNKT cell activation in the presence of TGF-β and IL-4 indu...


The fate of CD4+ T cells under tolerance‐inducing stimulation: a modeling persp...

Caridade, Marta; Oliveira, Vanessa; Agua-Doce, Ana; Graca, Luis; Ribeiro, Ruy

Non-depleting anti-CD4 monoclonal antibodies (MAbs) induce long-term dominant tolerance mediated by regulatory T cells in several animal models of transplantation, allergy and autoimmunity. However, despite many studies on tolerance induction following CD4 blockade, the consequences of this intervention on T-cell kinetics are still unknown. Mathematical models have been useful to understand lymphocyte dynamics,...


Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-b

Monteiro, Marta; Almeida, Catarina F.; Caridade, Marta; Ribot, Julie C.; Duarte, Joana; Agua-Doce, Ana; Wollenberg, Ivonne; Silva-Santos, Bruno

Invariant NKT (iNKT) cells were shown to prevent the onset of experimental autoimmune encephalomyelitis in mice following administration of their specific TCR agonist alpha-galactosylceramide. We found that this protection was associated with the emergence of a Foxp3(+) iNKT cell population in cervical lymph nodes. We demonstrate that the differentiation of these cells is critically dependent on TGF-beta in bot...


Modulation of IL-17 and Foxp3 expression in the prevention of autoimmune arthri...

Duarte, Joana; Agua-Doce, Ana; Oliveira, Vanessa G.; Fonseca, João Eurico; Graca, Luis

Background: Rheumatoid Arthritis (RA) is a chronic immune mediated disease associated with deregulation of many cell types. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells. Methodology and Findings: We investigated whether non-depleting anti-CD4 monoclonal antibodies, which have been reported as pro-tolerogenic, can lead to prot...


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