T cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T... Show moreT cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T cell responses. Using LCMV Clone-13 as a model of persistent viral infection, this thesis investigates the roles of IL-27 and IFN-I in regulating T cells during infection. In addition, the thesis explores the potential of JAK inhibitor in rescuing T cell exhaustion during persistent viral infection and cancer. Show less
Borst, L.; Sluijter, M.; Sturm, G.; Charoentong, P.; Santegoets, S.J.; Gulijk, M.; ... ; Hall, T. van 2021
The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in... Show moreThe surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A(+) CD8 T cell population in the context of other inhibitory receptors. Here we used a well-controlled culture system to study the kinetics of inhibitory receptor expression. Naive mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL-7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD-1, TIGIT and LAG-3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM-3 and CD39. Importantly, single-cell transcriptomics of human tumor-infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF-beta in vitro, although TGF-beta signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD-1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM-3 and CD39, NKG2A might thus mark actively dividing tumor-specific TILs. Show less
Resident memory CD8+ T cells (CD8+ TRM) play a central role in tissue immunity. This thesis focusses on the formation, function and behavior of CD8+ TRM in the skin. Firstly, by making use of... Show moreResident memory CD8+ T cells (CD8+ TRM) play a central role in tissue immunity. This thesis focusses on the formation, function and behavior of CD8+ TRM in the skin. Firstly, by making use of lineage tracing technology, we show that the capacity to form TRM is instilled in CD8+ T cells before the cells enter the affected tissue and that this capacity remains fixed after a secondary immune challenge. Second, this works shows that CD8+ skin-TRM act as local sentinels that trigger a rapid and tissue-wide immune response upon foreign antigen recognition. Third, ex vivo imaging of human skin biopsies demonstrates that tissue patrol is a property of CD8+ TRM in human skin. In addition, this work describes the development of two novel technologies (i.e. the ‘Tol’ mouse strain and the ex vivo imaging technique) that can be used as such or adapted by other biomedical researchers in order to investigate key aspects of (T) cell behavior and skin biology. Understanding the signals that drive CD8+ TRM formation, and insights in the function of these cells within both healthy and diseased skin, will be essential to allow the manipulation of these populations for therapeutic benefit. Show less
Hall, T. van; Andre, P.; Horowitz, A.; Ruan, D.F.; Borst, L.; Zerbib, R.; ... ; Vivier, E. 2019
Dendritic cells (DCs) express Fc receptors (FcRs) for the binding immune complexes (ICs) consisting of IgG and antigens (Ags). IC-FcR interactions have been demonstrated to enhance activation and... Show moreDendritic cells (DCs) express Fc receptors (FcRs) for the binding immune complexes (ICs) consisting of IgG and antigens (Ags). IC-FcR interactions have been demonstrated to enhance activation and antigen-presenting functions of DCs. Utilizing Friend virus (FV), an oncogenic mouse retrovirus, we investigated the effect of IgG-opsonization of retroviral particles on the infection of DCs and the subsequent presentation of viral antigens by DCs to virus-specific CD8 T cells. We found that opsonization by virus-specific non-neutralizing IgG abrogated DC infection and as a consequence significantly reduced the capacity of DCs to activate virus-specific CD8 T cells. Effects of IgG-opsonization were mediated by the high-affinity FcR type I, CD64, expressed on DCs. Our results suggest that different opsonization patterns on the retroviral surface modulate infection and antigen-presenting functions of DCs, whereby, in contrast to complement, IgG reduces the capacity of DCs to activate cytotoxic T cell (CTL) responses. Show less
Tumors can evade recognition by the immune system through downregulation of the peptide-presenting MHC-I molecules. In this thesis, we describe that these tumors can still be targeted by a... Show moreTumors can evade recognition by the immune system through downregulation of the peptide-presenting MHC-I molecules. In this thesis, we describe that these tumors can still be targeted by a novel category of CD8 T cells, recognizing a specific peptide presented on those immune-escaped tumors. We describe the selection and characteristics of these specific T cells and show they can protect against a challenge with these MHC-I low tumors. This could be a novel type of therapy for tumors which have become resistant against conventional (immune)therapies. Show less
