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The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to express a chimeric antigen receptor (CAR). Here, we will look into the history and recent developments of T and NK cell-based immunotherapy.
Post-transcriptional gene regulation through microRNA (miRNA) has emerged as a major control mechanism of multiple biological processes, including development and function of T cells. T cells are vital components of the immune system, with conventional T cells playing a central role in adaptive immunity and unconventional T cells having additional functions reminiscent of both innate and adaptive immunity, such as involvement in stress responses and tissue homeostasis. Unconventional T cells encompass cells expressing semi-invariant T cell receptors (TCRs), such as invariant Natural Killer T (iNKT) and Mucosal-Associated Invariant T (MAIT) cells. Additionally, some T cells with diverse TCR repertoires, including γδT cells, intraepithelial lymphocytes (IEL) and regulatory T (Treg) cells, share some functional and/or developmental features with their semi-invariant unconventional counterparts. Unconventional T cells are particularly sensitive to disruption of miRNA function, both globally and on the individual miRNA level. Here, we review the role of miRNA in the development and function of unconventional T cells from an iNKT-centric point of view. The function of single miRNAs can provide important insights into shared and individual pathways for the formation of different unconventional T cell subsets.
Acute graft-versus-host disease (GvHD) is still a major cause of treatment-related mortality after allogeneic stem cell transplantation. Allo-antigen recognition of donor T cells after transplantation account for the onset and persistence of this disease. MicroRNAs (miRNAs) are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation. Thus, miRNAs also contribute to pathological T-cell function during GvHD. Given their capacity of fine-tuning T-cell function, miRNAs have emerged as promising therapeutic targets to curtail acute GvHD, but simultaneously maintain T-cell-mediated graft-versus-tumor effects. Here, we review the role of key miRNAs contributing to the pathophysiology of GvHD. We focus on those miRNAs acting in T cells and for which a role in GvHD has been established in preclinical models. Finally, we provide an outlook for clinical application of this new therapeutic target for GvHD prevention and treatment.
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, “3Y”) as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells.
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.