In this study, we present evidence of differential Th17 responses in human monocyte-derived dendritic cells exposed to the pathogenic Candida albicans or the nonpathogenic Saccharomyces cerevisiae. ...We use different forms of the microorganisms, cells, hyphae, and spores, as a toolbox to dissect the role of surface mannan in the fungal immune response. In contrast to the S. cerevisiae yeast cell-induced Th1 response, dendritic cells stimulated with spores or C. albicans hyphae induce cellular responses shifted toward Th17 differentiation. The differential recognition of specific mannan structures is the master regulator of the discrimination between harmful and harmless fungi. The switch between spores and yeast is crucial for the commensalism of S. cerevisiae and depends on the use of a different receptor repertoire. Understanding the role of cell wall recognition during infection might lead to understanding the boundaries between safety and pathogenicity.
Inflammatory monocytes play important functions in antiviral immune responses, including release of inflammatory cytokines and antigen presentation to T lymphocytes. Depending on the pathological ...context, these functions might translate into beneficial or detrimental effects in the resolution of the disease. Recent literature has highlighted a role for inflammatory monocytes also in direct suppression of B cell responses. In this review, we will briefly discuss research showing the relationship between inflammatory monocytes and B lymphocytes, its functional consequences on antiviral antibody responses, and possible implications in the design of future vaccination strategies.
A genetic variant of the protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with a wide range of autoimmune diseases; however, the reasons behind its prevalence in the general ...population remain not completely understood. Recent evidence highlights an important role of autoimmune susceptibility genetic variants in conferring resistance against certain pathogens. In this study, we examined the role of PTPN22 in persistent infection in mice lacking PTPN22 infected with lymphocytic choriomeningitis virus clone 13. We found that lack of PTPN22 in mice resulted in viral clearance 30 days after infection, which was reflected in their reduced weight loss and overall improved health. PTPN22
mice exhibited enhanced virus-specific CD8 and CD4 T cell numbers and functionality and reduced exhausted phenotype. Moreover, mixed bone marrow chimera studies demonstrated no differences in virus-specific CD8 T cell accumulation and function between the PTPN22
and PTPN22
compartments, showing that the effects of PTPN22 on CD8 T cells are T cell-extrinsic. Together, these findings identify a CD8 T cell-extrinsic role for PTPN22 in weakening early CD8 T cell responses to collectively promote persistence of a chronic viral infection.
miR-21 is highly expressed in iNKT and activated T cells, but its T-cell autonomous functions are poorly defined. We sought to investigate the role of miR-21 in the development and functions of T and ...iNKT cells, representing adaptive and innate-like populations, respectively.
We studied mice with a conditional deletion of miR-21 in all mature T lymphocytes.
Thymic and peripheral T and iNKT compartments were normal in miR-21 KO mice. Upon activation
, miR-21 depletion reduced T-cell survival, T
17 polarisation and, remarkably, T- and iNKT cell ability to respond to low-affinity antigens, without altering their response to high-affinity ones. Mechanistically, miR-21 sustained CD28-dependent costimulation pathways required to lower the T-cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T-cell sensitivity to antigenic stimulation and survival. Upon immunisation with the low-affinity self-epitope MOG
, miR-21 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T-cell responses against high-affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection.
The induction of T-cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR-21 sustains CD28 costimulation, decreasing the T-cell activation threshold and increasing their sensitivity to antigenic stimulation and survival, broadening the immune surveillance range. This occurs at the cost of unleashing autoimmunity, resulting from the recognition of weak self-antigens by autoreactive immune responses. Thus, miR-21 fine-tunes T-cell response and self-/non-self-discrimination.
Intraepithelial lymphocytes (IELs) are tissue-resident immune cells that surveil the intestine and provide the first line of defense against pathogens. Reporting in Cell, van Konijnenburg et al. ...(2017) combine high-resolution microscopy and intersectional genetic tools to provide a detailed characterization of IEL dynamics in response to both commensal and pathogenic microorganisms.
Intraepithelial lymphocytes (IELs) are tissue-resident immune cells that surveil the intestine and provide the first line of defense against pathogens. Reporting in Cell, van Konijnenburg et al. (2017) combine high-resolution microscopy and intersectional genetic tools to provide a detailed characterization of IEL dynamics in response to both commensal and pathogenic microorganisms.
•Type I IFNs act at different levels to promote CD4+ T cell expansion during acute infections.•Type I IFNs released upon chronic viral infection induce CD4+ T cell exhaustion.•The role of type I IFNs ...on CD4+ T cell polarization is debated, and probably depends on the concomitant inflammatory milieu.
Type I interferons (IFNs) released upon viral infections play different and opposing roles in disease outcome. This pleiotropic effect is mainly influenced by the cellular sources, timing and target cells for these molecules. The effect of type I IFN signaling on the activation and differentiation of antiviral CD4+ T cells remains ill defined, with studies reporting either a beneficial or a detrimental role, depending on the context of infection. This review will highlight several recent studies that have investigated the role of type I IFNs in the priming and polarization of CD4+ T cells and discuss areas of uncertainty that require further investigation.
Pathogen recognition by dendritic cells (DC) is crucial for the initiation of both innate and adaptive immune responses. Activation of Toll-like Receptors (TLRs) by microbial molecular patterns leads ...to the maturation of DC, which present the antigen and activate T cells in secondary lymphoid tissues. Cytokine production by DC is critical for shaping the adaptive immune response by regulating T helper cell differentiation. It was previously shown by our group that Src kinases play a key role in cytokines production during TLR4 activation in human DC.
In this work we investigated the role of Src kinases during different TLRs triggering in human monocyte-derived DC (MoDC). We found that Src family kinases are important for a balanced production of inflammatory cytokines by human MoDC upon stimulation of TLR3 and 8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the DC maturation pattern. In particular, while expression of IL-12 and other inflammatory cytokines depend on Src kinases, the induction of IL-23 and co-stimulatory molecules do not. Accordingly, DC treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the Th17 subset survival but are less efficient in inducing Th1 differentiation.
We suggest that the pharmacological modulation of DC maturation has the potential to shape the quality of the adaptive immune response and could be exploited for the treatment of inflammation-related diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Humoral immune responses depend on B cells encountering antigen (Ag) in lymph nodes (LNs) draining infection sites, getting activated, interacting with different cells, proliferating and ...differentiating into antibody (Ab)-secreting cells. Each of these events occurs in distinct LN sub-compartments, requiring the migration of B cells from niche to niche in a fast and tightly coordinated fashion. While some of the rules that characterize B cell behavior in secondary lymphoid organs have been elucidated at the population level, we have only limited knowledge of the precise dynamics of B cell interactions with different kinds of LN cells at the single-cell level. Here, we describe in detail an intravital microscopy technique that allows the analysis of B cell dynamic behavior in the popliteal lymph node of anesthetized mice at high spatial and temporal resolution. A detailed understanding of the spatiotemporal dynamics of B cells within secondary lymphoid organs may lead to novel, rational vaccine strategies aimed at inducing rapid and long-lived humoral immune responses.
Abstract
Although humoral and cellular immunity upon viral infections usually co-exist, sometimes one of the two responses emerges and is responsible for most of the antiviral activity. For example, ...vescicular stomatitis virus (VSV) infection induces early and potent neutralizing antibody (nAb) responses, whereas lymphocytic choriomeningitis virus (LCMV) infection induces strong cellular responses, but weak nAb responses. Recent work from our laboratory has shown that unbalance is observed also at the level of CD4 T cells responses, with VSV inducing strong TFH polarization that support nAb responses, and LCMV in contrast promoting TH1 differentiation. Analysis of the VSV and LCMV priming niches led to identification of the spatiotemporal regulation of type I IFN expression as a critical regulator of antiviral CD4+ T cell polarization, with early type I IFN sensing leading to TFH polarization. Notably, this mechanism did not explain the strong TH1 differentiation observed during LCMV infection. In this study we aimed to elucidate the role of known TH1-polarizing cytokines in CD4+ T cell differentiation upon LCMV infection. We found that IFN-γ, but not IL-12, plays a key role in early CD4+ T cell differentiation upon LCMV infection, inducing TH1 cell polarization and suppressing TFH cell development, thus resulting in a shift in the equilibrium towards TFH and humoral responses. Future studies will determine the cellular source for this TH1-polarizing cytokine and the mechanism by which IFN-γ exerts its function, possibly unveiling the mechanisms underlying the reduced humoral response in the context of viral infections like LCMV.
Abstract
TDC are hematopoietic cells that combine dendritic cell (DC) and conventional T cell markers and functional properties. They were identified in secondary lymphoid organs (SLO) of naïve mice ...as cells expressing CD11c, MHC-II, and TCRβ chain. TDC expand in response to TCR-mediated stimulation, but they also express the DC lineage marker Zbtb46. Moreover, TDC are characterized by a cytotoxic gene signature, including high expression of IFNγ and granzymes. Unfortunately, using CD11c as a marker for TDC has the caveat of its upregulation on different cells (including T cells) upon activation. Therefore, a more specific marker could be useful to further investigate TDC functions in peripheral organs or during inflammation. We exploited the unique genetic profile of TDC to obtain a reporter mouse model in which TDC are marked with two different fluorescent proteins (Zbtb46-GFP and Gzmb-Tomato). This model allowed us to use Zbtb46 instead of CD11c as a marker for TDC, in order to investigate the frequency and localization of TDC in peripheral tissues such as liver, small intestine, and lung. RNA sequencing analysis confirmed that TDC identified with this reporter model have an overlapping gene signature with the one already reported for TDC. In addition, frequency and total numbers of Zbtb46+ TDC in the SLO recapitulated those previously found using CD11c, thus confirming the validity of our model. Interestingly, we found that TDC numbers in the SLO increased upon LCMV infection, indicating that TDC might play a role during viral infections. Further studies aimed at identifying the localization of TDC in peripheral organs, and their role in several pathological settings are ongoing.
M.K. is supported by the Italian Ministry of Education, University and Research grants SIR-RBSI14BAO5 and PRIN-2017ZXT5WR
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