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iNKT cells: innate lymphocytes with a diverse response
Publication . Monteiro, Marta; Graca, Luis
It is now established that natural killer T (NKT) cells can influence adaptive immune responses by producing vast amounts of cytokines. Different subsets of NKT cells with distinctive functional characteristics regarding cytokine production have been described. This is the case for NKT1, NKT2, or NKT17 that resemble conventional CD4 Th1, Th2, and Th17 cells in the cytokines they produce. Unlike conventional CD4 T cells that mostly acquire functional specialization in the periphery, a number of NKT cells become specialized effectors during thymic development. This opinion article describes the evidence for an extrathymic commitment of specialized NKT-cell subsets that, together with thymic lineages, contributes to the overall functional diversity of NKT cells participating in immune responses in the periphery.
IL-9 expression by invariant NKT cells is not imprinted during thymic development
Publication . 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 induces IL-9 secretion in murine and human iNKT cells. Acquisition of IL-9 production was observed in different iNKT subsets defined by CD4, NK1.1, and neuropilin-1, indicating that distinct functional subpopulations are receptive to IL-9 polarization. Transcription factor expression kinetics suggest that regulatory mechanisms of IL-9 expression are shared by iNKT and CD4 T cells, with Irf4 and Batf deficiency deeply affecting IL-9 production. Importantly, adoptive transfer of an enriched IL-9(+) iNKT cell population leads to exacerbated allergic inflammation in the airways upon intranasal immunization with house dust mite, confirming the ability of IL-9-producing iNKT cells to mediate proinflammatory effects in vivo, as previously reported. Taken together, our data show that peripheral iNKT cells retain the capacity of shaping their function in response to environmental cues, namely TGF-β and IL-4, adopting an IL-9-producing NKT cell phenotype able to mediate proinflammatory effects in vivo, namely granulocyte and mast cell recruitment to the lungs.
The fate of CD4+ T cells under tolerance‐inducing stimulation: a modeling perspective
Publication . 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, estimating rates of proliferation and cell death following an intervention. Using the same strategy, we found that CD4(+) T cells activated in vitro in the presence of non-depleting anti-CD4 MAbs are prevented from undergoing optimal proliferation and show a higher frequency of apoptosis. Although the changes are small, during the course of a proliferative response, they lead to very distinct final levels of cell numbers. The importance of these mechanisms, predicted by the mathematical model, was validated by showing that lck-driven Bcl-x(L) transgenic mice, bearing T cells resistant to apoptosis, fail to become tolerant to skin grafts following CD4-blockade. Our data show that, in addition to induction of regulatory T cells, CD4 blockade has a marked effect in the effector T-cell pool by the combined action of hindering proliferation while favoring apoptosis. It is, therefore, the combination of all those mechanisms that leads to stable tolerance.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/SAU-TOX/114424/2009