Human γδ T Lymphocytes Are Licensed for Professional Antigen Presentation by Interaction with Opsonized Target Cells

Abstract

Activated human blood γδ T cells have also been previously demonstrated to behave as professional APCs, although the processes that control APC function have not been characterized. n this study, we show that the acquisition of potent APC function by human blood γδ T cells is achieved after physical interaction with an Ab-coated target cell, a process that we refer to as licensing. In cancer models, licensing of γδ T cells by tumor-reactive mAbs promotes the uptake of tumor Ags and professional presentation to tumor-reactive αβ T cells. We propose that licensing by Ab is a mechanism whereby the adaptive properties of γδ T cells are induced by their innate functions in a spatially and temporally controlled manner.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Activated Vc9/ Vd2 T cells turned out to be well equipped cross-presenting APCs capable of processing not only defined proteins but also complex material such as cell debris and whole bacteria, and shuttle endocytosed antigens into the cytosol for degradation by the proteasome [118][119][120]. As Vc9/Vd2 T cells retain their cytolytic potential when they acquire APC functions [127], this unique combination of direct target cytotoxicity and APC machinery allows for scenarios in which Vc9/Vd2 T cells would lyse transformed, stressed or infected cells, and take up and process released proteins for presentation to both CD4 + and CD8 + T cells, with enormous implications for novel immunotherapies and vaccines [128][129][130][131][132]. In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134].…”

“…As Vc9/Vd2 T cells retain their cytolytic potential when they acquire APC functions [127], this unique combination of direct target cytotoxicity and APC machinery allows for scenarios in which Vc9/Vd2 T cells would lyse transformed, stressed or infected cells, and take up and process released proteins for presentation to both CD4 + and CD8 + T cells, with enormous implications for novel immunotherapies and vaccines [128][129][130][131][132]. In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134]. Such a licensing pathway to boost cross-presentation of tumor-derived antigens could be exploited by using monoclonal antibodies specifically targeting tumor cells, such as rituximab (anti-CD20), trastuzumab (anti-HER2/neu) or ch14.18 (anti-GD2), and contribute to the effectiveness of combination therapies [135][136][137].…”

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

“…A number of groups based at University College London are developing technologies that are at various levels of clinical development, including engineering lymphocytes with sort-suicide transgenes, 64 TCRs specific for viral antigens, 46 selection of adenoviral-specific T-cells for adoptive transfer, 65 and the examination of T-cell subsets for adoptive T-cell therapy. 66 …”

Combination Strategies to Enhance the Potency of Monocyte-Derived Dendritic Cell-Based Cancer Vaccines

“…Also, an emerging model suggests that 'licensed' human γδ T cells operate as potent professional APCs similar to DC by cross-presenting exogenous antigen to tumor-reactive αβ T cells. The full licensing of γδ T cells requires the interaction of γδ T cell CD16 with antibody-opsonized tumor cells following γδ TCR ligation at tumor site [80,81]. Therapies incorporating licensed γδ T cells as antigen presenting cells in combination with monoclonal antibody therapy may represent an effective cancer treatment strategy in future.…”