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Abstract: Emerging evidence indicates that a dynamic interplay between the immune system and adipocytes contributes to the disturbed homeostasis in adipose tissue of obese subjects. Recently, we observed IL‐6‐secretion by CD4+ T cells from the stromal vascular fraction (SVF) of the infrapatellar fat pad (IFP) of knee osteoarthritis patients directly ex vivo. Here we show that human IL‐6+CD4+ T cells from SVF display a more activated phenotype than the IL‐6− T cells, as evidenced by the expression of the activation marker CD69. Analysis of cytokines secretion, as well as expression of chemokine receptors and transcription factors associated with different Th subsets (Treg, Th1, Th2, Th17 and Tfh) revealed that IL‐6‐secreting CD4+ T cells cannot be assigned to a conventional Th subset. TCRβ gene analysis revealed that IL‐6+ and IL‐6−CD4+ T cells appear clonally unrelated to each other, suggesting a different specificity of these cells. In line with these observations, adipocytes are capable of enhancing IL‐6 production by CD4+ T cells. Thus, IL‐6+CD4+ T cells are TCRαβ T cells expressing an activated phenotype potentially resulting from an interplay with adipocytes that could be involved in the inflammatory processes in the OA joint. [ABSTRACT FROM AUTHOR]

Basophils are mostly known for their involvement in allergic reactions. Recent studies in mice indicate a role for basophils in the induction of adaptive immunity, especially T helper 2 ( Th2) responses. Therefore, it would be highly important to understand how basophils respond to pathogen-associated molecules, such as ligands for toll-like receptors ( TLRs), and if the basophils could promote Th2 responses via these stimuli. To this end, the activation of basophils via TLRs in combination with activation via Ig E was studied, as well as its effect on T helper cell skewing. Using quantitative PCR, we demonstrated the presence of m RNA for TLRs 1-8 in human basophils. Basophils responded to TLR triggering with differential cytokine production, but not with degranulation. Simultaneous triggering of TLRs and Ig E led to synergy in production of IL-4, IL-8, IL-13, and RANTES. Furthermore, the synergistic effects on basophils mediated by Ig E and TLR-4 triggering allowed robust Th2 skewing upon activation of naïve human CD4+ T cells. Our data show that human basophils respond to TLR ligands in synergy with Ig E-mediated activation and that the cytokines produced can promote Th2 differentiation. These results indicate a role for basophils in the regulation of T-cell responses in humans. [ABSTRACT FROM AUTHOR]

Adipose tissue contains several immune cells whose number and phenotype vary depending on the adiposity. In the present study, we show that IFN-γ+ CD4+ T cells are enriched in human adipose tissue compared with in blood. To gain insight into the underlying mechanisms, we investigated the possibility that human adipocytes modulate CD4+ T-cell cytokine production and proliferation and show that CD4+ T cells produced increased levels of IFN-γ when activated in the presence of adipocytes. This effect was mediated by soluble mediators, as shown in transwell and adipocyte-conditioned medium (ACM) transfer experiments. Additionally, ACM induced increased proliferation of CD4+ T cells upon activation. Intriguingly, the proliferation-enhancing effect resided mainly in the lipid fraction of ACM, as shown upon separation of the protein and lipid fraction. Further separation of these lipids based on polarity revealed that the modulatory effect is confined to fractions containing free fatty acids. All identified fatty acids were able to individually enhance T-cell proliferation. These data indicate that adipocytes can modulate CD4+ T-cell function through the release of lipids. Remarkably, free fatty acids were the most prominent modulators of T-cell proliferation, possibly leading to an accumulation of these cells in adipose tissue. [ABSTRACT FROM AUTHOR]

DX5+ CD4+ T cells have been shown to dampen collagen-induced arthritis and delayed-type hypersensitivity reactions in mice. These cells are also potent modulators of T-helper cell responses through direct effects on CD4+ T cells in an IL-4 dependent manner. To further characterize this T-cell population, we studied their effect on DCs and the potential consequences on T-cell activation. Here, we show that mouse DX5+ CD4+ T cells modulate DCs by robustly inhibiting IL-12 production. This modulation is IL-10 dependent and does not require cell contact. Furthermore, DX5+ CD4+ T cells modulate the surface phenotype of LPS-matured DCs. DCs modulated by DX5+ CD4+ T-cell supernatant express high levels of the co-inhibitor molecules PDL-1 and PDL-2. OVA-specific CD4+ T cells primed with DCs exposed to DX5+ CD4+ T-cell supernatant produce less IFN-γ than CD4+ T cells primed by DCs exposed to either medium or DX5− CD4+ T-cell supernatant. The addition of IL-12 to the co-culture with DX5+ DCs restores IFN-γ production. When IL-10 present in the DX5+ CD4+ T-cell supernatant is blocked, DCs re-establish their ability to produce IL-12 and to efficiently prime CD4+ T cells. These data show that DX5+ CD4+ T cells can indirectly affect the outcome of the T-cell response by inducing DCs that have poor Th1 stimulatory function. [ABSTRACT FROM AUTHOR]

CD4 [ABSTRACT FROM AUTHOR]

CD4 T cells are important for CD8 T-cell priming by providing cognate signals for DC maturation. We analyzed the capacity of CD4 T cells to influence CD8 T-cell responses induced by activated DC. Surprisingly, mice depleted for CD4 cells were able to generate stronger antigen-specific CD8 T-cell responses after DC vaccination than non-depleted mice. The same observation was made when mice were vaccinated with MHC class II DC, indicating the presence of a MHC class II-dependent CD4 T-cell population inhibiting CD8 T-cell responses. Recently we described the expansion of DX5CD4 T cells, a T-cell population displaying immune regulatory properties, upon vaccination with DC. Intriguingly, we now observe an inverse correlation between CD8 T-cell induction and expansion of DX5CD4 T cells as the latter cells did not expand after vaccination with MHC class II DC. In vitro, DX5CD4 T cells were able to limit proliferation, modulate cytokine production and induce Foxp3 expression in OVA-specific CD8 T cells. Together, our data show an inhibitory role of CD4 T cells on the induction of CD8 T-cell responses by activated DC and indicate the involvement of DX5CD4, but not CD4CD25, T cells in this process. [ABSTRACT FROM AUTHOR]

The immune response against human adenovirus (HAdV) has gained interest because of the application of HAdV-based vectors in gene therapy and the high incidence of infections in pediatric recipients of allogeneic stem cell grafts. Because antiviral medication is frequently ineffective, the option of adoptive transfer of HAdV-specific donor-derived T cells in these immunocompromised patients is investigated. To generate good manufacturing practice-compatible reagents, a panel of 63 long, overlapping, peptides of the hexon protein was screened for recognition by T cells. Five conserved peptides of 30 amino acids were identified that were recognized by the majority of adult donors. CD4 T cells from long-term cultures of PBMC, stimulated with this set of five peptides, recognized cells infected with HAdV serotypes belonging to different species. These data demonstrate that adult human T cells preferentially recognize conserved sequences of amino acid residues from a structural protein of HAdV. In the context of gene therapy, this observation may limit the beneficial effect of switching to HAdV-based vectors derived from less common serotypes of HAdV in an attempt to circumvent pre-existing immunity. However, this cross-reactivity benefits the application of HAdV-specific T cells for adoptive immunotherapy in immunocompromised transplant recipients. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that a dynamic interplay between the immune system and adipocytes contributes to the disturbed homeostasis in adipose tissue of obese subjects. Recently, we observed IL-6-secretion by CD4 + T cells from the stromal vascular fraction (SVF) of the infrapatellar fat pad (IFP) of knee osteoarthritis patients directly ex vivo. Here we show that human IL-6 + CD4 + T cells from SVF display a more activated phenotype than the IL-6 - T cells, as evidenced by the expression of the activation marker CD69. Analysis of cytokines secretion, as well as expression of chemokine receptors and transcription factors associated with different Th subsets (Treg, Th1, Th2, Th17 and Tfh) revealed that IL-6-secreting CD4 + T cells cannot be assigned to a conventional Th subset. TCRβ gene analysis revealed that IL-6 + and IL-6 - CD4 + T cells appear clonally unrelated to each other, suggesting a different specificity of these cells. In line with these observations, adipocytes are capable of enhancing IL-6 production by CD4 + T cells. Thus, IL-6 + CD4 + T cells are TCRαβ T cells expressing an activated phenotype potentially resulting from an interplay with adipocytes that could be involved in the inflammatory processes in the OA joint., (© 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Basophils are circulating granulocytes, best known as effector cells in allergic reactions. Recent studies in mice suggest that they might also participate in the suppression of chronic inflammation. The aim of this study was to assess the ability of purified human basophils to modulate monocyte responses upon IL-33 and IgE triggering. Activation of human basophils with IL-33 induced the production of IL-4 and the release of histamine, and enhanced their IgE-mediated activation. In addition, basophils triggered with IL-33 and anti-IgE significantly suppressed the LPS-induced production of the proinflammatory cytokine TNF-α and the upregulation of the costimulatory molecule CD80 by monocytes. These effects were mainly explained by the release of histamine, as they could be inhibited by the histamine receptor 2 antagonist ranitidine, with a smaller contribution of IL-4. In contrast, basophil-derived IL-4 and histamine had opposing effects on the expression of the inhibitory Fc γ receptor IIb and the production of IL-10 by monocytes. Our data show that basophils can influence monocyte activation and suggest a previously unrecognized role for human basophils in the modulation of monocyte-mediated immune responses, through the balanced secretion of histamine and IL-4., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mast cells (MCs) are immune cells residing in tissues where pathogens are first encountered. It has been indicated that MCs might also be involved in setting the outcome of T-cell responses. However, little is known about the capacity of human MCs to express MHC class II and/or to capture and present antigens to CD4(+) T cells. To study the T-cell stimulatory potential of human MCs, CD34(+) stem cell derived MCs were generated. These cells expressed HLA-DR when stimulated with IFN-γ, and, importantly, presented peptide and protein for activation of antigen-specific CD4(+) T cells. The interplay between MC and T cell led to increased HLA-DR expression on MCs. MCs were present in close proximity to T cells in tonsil and expressed HLA-DR and CD80, indicating their ability to present antigens to CD4(+) T cells in T-cell areas of human LNs. Our data show that MCs can present native antigens to human CD4(+) T cells and that HLA-DR expressing MCs are present in tonsil tissue, indicating that human MCs can directly activate T cells and provide a rationale to study the potential of MCs to prime and/or skew human T-cell responses., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

CD4(+) T cells are important for CD8(+) T-cell priming by providing cognate signals for DC maturation. We analyzed the capacity of CD4(+) T cells to influence CD8(+) T-cell responses induced by activated DC. Surprisingly, mice depleted for CD4(+) cells were able to generate stronger antigen-specific CD8(+) T-cell responses after DC vaccination than non-depleted mice. The same observation was made when mice were vaccinated with MHC class II(-/-) DC, indicating the presence of a MHC class II-dependent CD4(+) T-cell population inhibiting CD8(+) T-cell responses. Recently we described the expansion of DX5(+)CD4(+) T cells, a T-cell population displaying immune regulatory properties, upon vaccination with DC. Intriguingly, we now observe an inverse correlation between CD8(+) T-cell induction and expansion of DX5(+)CD4(+) T cells as the latter cells did not expand after vaccination with MHC class II(-/-) DC. In vitro, DX5(+)CD4(+) T cells were able to limit proliferation, modulate cytokine production and induce Foxp3(+) expression in OVA-specific CD8(+) T cells. Together, our data show an inhibitory role of CD4(+) T cells on the induction of CD8(+) T-cell responses by activated DC and indicate the involvement of DX5(+)CD4(+), but not CD4(+)CD25(+), T cells in this process.

To investigate the influence of avidity on T cell activation in vitro and in vivo, we analyzed T cells from St40 and St42 mice, which express the same transgenic TCR specific for an E1a-derived epitope of adenovirus type 5 with different expression levels and therefore different avidities. Splenocytes from both strains showed comparable cytolytic activities and required identical peptide concentrations for efficient target cell lysis and up-regulation of activation markers. However, the kinetics of CD25 up-regulation were strikingly different: whereas the majority of the high-avidity St42 T cells up-regulated the IL-2Ralpha chain within a few hours, low-avidity St40 T cells expressed only 50% of the CD25 of high-avidity T cells after 2 days. In addition, low-avidity T cells proliferated poorly and displayed impaired secretion of IL-2 and IFN-gamma. Similar results were seen with high-avidity St42 T cells stimulated with a partial agonistic peptide. Upon adoptive transfer and subsequent immunization with adenovirus, both high- and low-avidity T cells expanded, but St40 T cells were undetectable 10 days after immunization. Our model system now allows analysis of whether T cells with identical specificities but different avidities influence each other during activation and homeostatic proliferation.