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Peripheral clonal selection shapes the human γδ T-cell repertoire
Publication . Di Lorenzo, Biagio; Déchanet-Merville, Julie; Silva-Santos, Bruno
γδ T cells are often placed at the interface between innate and adaptive immunity. These cells share T-cell receptor (TCR) rearrangements and memory functions in common with their αβ T-cell counterparts but differ in terms of their response kinetics and mechanisms of target recognition (Figure 1). Indeed, γδ T cells provide fast responses against infected or transformed cells in a major histocompatibility complex-independent manner, thus participating in the first line of defense, which gives the organism time to mount antigen-specific αβ T-cell responses. Although the four TCR loci were discovered and characterized almost simultaneously, our knowledge of the mechanisms underlying γδ T-cell responses remains insufficient. However, an increasing amount of evidence has demonstrated that γδ T cells recognize self-antigens on the surface of target cells; the expression of these self-antigens is known or expected to increase upon stress, infection or transformation in a TCR-dependent manner, making them an attractive source for cell-based immunotherapies. This response is noted in the case of BTN3A associated with phosphoantigens, lipid-presenting CD1 molecules, endotelial protein C receptor and Annexin A. However, these molecules constitute only a small fraction of the ligands recognized by γδ T cells. In addition, the mechanism by which the γδ TCR repertoire is shaped under physiological conditions and how (much) it changes in response to pathogenic challenge remain poorly understood.
Molecular determinants of target cell recognition by human γδ T Cells
Publication . Simões, André; Di Lorenzo, Biagio; Silva-Santos, Bruno
The unique capabilities of gamma-delta (γδ) T cells to recognize cells under stressed conditions, particularly infected or transformed cells, and killing them or regulating the immune response against them, paved the way to the development of promising therapeutic strategies for cancer and infectious diseases. From a mechanistic standpoint, numerous studies have unveiled a remarkable flexibility of γδ T cells in employing their T cell receptor and/or NK cell receptors for target cell recognition, even if the relevant ligands often remain uncertain. Here, we review the accumulated knowledge on the diverse mechanisms of target cell recognition by γδ T cells, focusing on human γδ T cells, to provide an integrated perspective of their therapeutic potential in cancer and infectious diseases.
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Fundação para a Ciência e a Tecnologia
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PD/BD/105880/2014