INTEGRATION OF RECEPTOR SIGNALING PATHWAYS IN THE DIFFERENTIATION AND FUNCTIONAL ACTIVATION OF HUMAN T LYMPHOCYTES

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Five layers of receptor signaling in γδ T-Cell differentiation and activation

Publication . Ribeiro, Sérgio T; Ribot, Julie; Silva-Santos, Bruno

The contributions of γδ T-cells to immunity to infection or tumors critically depend on their activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are molecularly controlled by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate γδ T-cell physiology. The understanding of how environmental signals are integrated by γδ T-cells is critical for their manipulation in clinical settings. Here, we discuss how different classes of surface receptors impact on human and murine γδ T-cell differentiation, activation, and expansion. In particular, we review the role of five receptor types: the T-cell receptor (TCR), costimulatory receptors, cytokine receptors, NK receptors, and inhibitory receptors. Some of the key players are the costimulatory receptors CD27 and CD28, which differentially impact on pro-inflammatory subsets of γδ T-cells; the cytokine receptors IL-2R, IL-7R, and IL-15R, which drive functional differentiation and expansion of γδ T-cells; the NK receptor NKG2D and its contribution to γδ T-cell cytotoxicity; and the inhibitory receptors PD-1 and BTLA that control γδ T-cell homeostasis. We discuss these and other receptors in the context of a five-step model of receptor signaling in γδ T-cell differentiation and activation, and discuss its implications for the manipulation of γδ T-cells in immunotherapy.

2015Artigo científico

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Molecular mechanisms controlling the survival and differentiation of human yσ thymocytes

Publication . Ribeiro, Sérgio Tiago de Freitas, 1989-; Santos, Bruno Silva, 1973-

Among the various leukocyte populations that build up the immune defense against infections and tumors, γδ T lymphocytes constitute an enigmatic lineage whose molecular mechanisms of differentiation and activation are still poorly understood. The key roles played by γδ T cells in immunity critically depend on their survival, activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are controlled, at the molecular level, by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate both lymphocyte physiology and pathology. In this PhD thesis we evaluated the contribution of cell receptor signaling pathways to human γδ T cell differentiation and activation. Firstly, we showed that human γδ thymocytes are functionally immature and their differentiation program requires additional IL-2 or IL-15 signals to drive their differentiation into IFN-γ and TNF-α producers endowed with potent cytotoxicity against leukemia targets. We further elucidated the signals involved in normal/ healthy γδ T cell maintenance as well as in γδ T cell tumorigenesis. We identified that the protein kinase CK2 (Casein Kinase 2) is overactivated in the γδ T cell lineage compared to αβ counterparts. We further showed that the clinical grade-inhibitor of CK2, CX- 4945, impairs γδ T cell survival by inhibiting the CK2/AKT/mTOR/GSK3β signaling pathway. Moreover, we showed that CK2 is hyperactivated in γδ T acute lymphoblastic leukemia (T-ALL) samples, compared to both normal γδ T cells and αβ T-ALL. Importantly, we demonstrated a high sensitivity of γδ T-ALL cells to CX- 4945 treatment in vitro and in vivo, thus supporting the use of CK2 inhibitors as a putative therapy for γδ T-ALL. Overall, the data presented in this thesis provided new evidences indicating that: (i) human γδ thymocytes are functionally immature and require IL-2 or IL-15 to differentiate into type 1 cytotoxic effector lymphocytes; (ii) the protein kinase CK2 is a novel determinant of both healthy and leukemic γδ T cell survival; and (iii) the CX-4945 chemical inhibitor is a promising therapeutic approach for γδ T-ALL.

2017Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/84123/2012