Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Abstract

Human plasmacytoid dendritic cells (pDC) are important modulators of adaptive T cell responses during viral infections. Recently, we found that human pDC produce the serine protease granzyme B (GrB), thereby regulating T cell proliferation in a GrB-dependent manner. In this study, we demonstrate that intrinsic GrB production by pDC is significantly inhibited in vitro and in vivo by clinically used vaccines against viral infections such as tick-borne encephalitis. We show that pDC GrB levels inversely correlate with the proliferative response of coincubated T cells and that GrB suppression by a specific Ab or a GrB substrate inhibitor results in enhanced T cell proliferation, suggesting a predominant role of GrB in pDC-dependent T cell licensing. Functionally, we demonstrate that GrBhigh but not GrBlow pDC transfer GrB to T cells and may degrade the ζ-chain of the TCR in a GrB-dependent fashion, thereby providing a possible explanation for the observed T cell suppression by GrB-expressing pDC. Modulation of pDC-derived GrB activity represents a previously unknown mechanism by which both antiviral and vaccine-induced T cell responses may be regulated in vivo. Our results provide novel insights into pDC biology during vaccinations and may contribute to an improvement of prophylactic and therapeutic vaccines.

CD4+ T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

“…As outlined in the Results section, we found that GraB cells from HIV patients directly suppressed TCR-z-chain levels of coincubated CD4 + T cells in a GrB-dependent manner, thereby impairing the proliferative response of T cells from HIV patients. Of note, support for our results comes from further studies demonstrating that in vitro-generated GrB-expressing cells, such as plasmacytoid dendritic cells, are also able to degrade the TCR-z-chain and to suppress T cell proliferation in a GrB-dependent manner (18,41,42). Thus, the disturbed interaction between B cells and T cells in HIV patients may result in a vicious circle between both cell types, further aggravating the cellular immune defect that develops during HIV infection (Fig.…”

Human Immunodeficiency Virus Arrests Plasmacytoid Dendritic Cells in a Granzyme Bhigh Tolerogenic State

“…This allows GzmB to reach the cytosol of target cells after exocytosis, where it may then activate apoptosis-inducing enzymes including caspases, DNAses and BID [1]. In contrast, certain immune cells including plasmacytoid dendritic cells (pDC) and B cells can produce GzmB only, but not Pfn [6,[10][11][12]. GzmB secreted by these APC types therefore primarily encounters substrates with an extracellular or membrane-close localisation such as extracellular proteins or membrane-bound receptors [8].…”

“…GzmB secreted by these APC types therefore primarily encounters substrates with an extracellular or membrane-close localisation such as extracellular proteins or membrane-bound receptors [8]. As a result, these cells develop a strong immunoregulatory potential based on GzmBdependent cleavage of the T cell receptor (TCR)-ζ-chain [6,[9][10][11][12][13]. Degradation of the TCR-ζ-chain by GzmB directly limits the proliferative capacity and survival of effector T cells.…”

The Dark Side of Dendritic Cells: Development and Exploitation of Tolerogenic Activity That Favor Tumor Outgrowth and Immune Escape

“…In murine models, the constitutively expressed Dll4 allow PDC to induce Th1 cells to produce IL-10 even under type 1 polarizing conditions, thus favoring the shut down of an immune response (123). Granzyme B, whose secretion by PDC is boosted by tumor-derived IL-3 and IL-10, is involved in the downregulation of the CD3ζ chain of T effector cells, thereby resulting in their anergy or deletion by apoptosis induction (124, 125). …”

“…At the basis of the positive outcome upon PDC in situ triggering there can be not only the activation of other immune cells and the inhibition of Treg (167), but also a direct tumoricidal activity upon upregulation of TRAIL and granzyme B (168, 169). Is to be underlined that the upregulation of granzyme B by PDC can also have detrimental effect by killing T cells (124, 125, 169). An other reported effect of CpG injection is the differentiation of MDSC toward functional monocytes with consequent reduction in the amount of suppressive cells (170, 171).…”