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CD4 + and CD4 2 cDC are equivalent in their ability to activate CD4 + T lymphocytes. (A) Splenic CD4 + and CD4 2 cDC were sorted on the basis of CD11c, CD11b, CD8 and CD4 expression. The presence of contaminating plasmacytoid DC and CD8a + cDC precursors in the CD4 2 cDC fraction was evaluated by using anti-Siglec-H and Sirp-a mAbs, respectively. (B, C) Both cDC subsets were sensitized with graded doses of OVA peptide (B) or whole OVA (C) and co-cultured for 3 and 5 days with naive CD4 + T cells purified from OT-II mice. The production of IFN-c and IL-13 was quantified by ELISA. Results represent the mean 6 SD of a representative experiment out of two. doi:10.1371/journal.pone.0026919.g001
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One important function of conventional dendritic cells (cDC) is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α(+) and CD8α(-) cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4(-) a...
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Context 1
... address this issue, CD8a 2 cDC subsets were purified from the spleens of naı¨venaı¨ve mice on the basis of CD11c, CD4, CD8 as well as CD11b expression. In contrast to previous reports, the CD11b marker was considered in our sorting strategy to limit contaminating cells, principally in the CD4 2 cDC fraction ( Figure 1A). Thus, all CD8a 2 cDC were CD11b + and the CD4 2 cDC subset contained very few contaminating cells, such as plasmacytoid DC (Siglec-H + ) or CD8 + cDC precursors (Sirp-a 2 ) ( Figure 1A). ...
Context 2
... contrast to previous reports, the CD11b marker was considered in our sorting strategy to limit contaminating cells, principally in the CD4 2 cDC fraction ( Figure 1A). Thus, all CD8a 2 cDC were CD11b + and the CD4 2 cDC subset contained very few contaminating cells, such as plasmacytoid DC (Siglec-H + ) or CD8 + cDC precursors (Sirp-a 2 ) ( Figure 1A). Isolated splenic CD4 + and CD4 2 cDC subsets were then assayed for their ability to prime and direct the differentiation of OVA-specific TCR transgenic T cells (OT-II) in steady-state conditions. ...
Context 3
... 2 cDC subset contained very few contaminating cells, such as plasmacytoid DC (Siglec-H + ) or CD8 + cDC precursors (Sirp-a 2 ) ( Figure 1A). Isolated splenic CD4 + and CD4 2 cDC subsets were then assayed for their ability to prime and direct the differentiation of OVA-specific TCR transgenic T cells (OT-II) in steady-state conditions. As seen in Fig. 1B, CD4 + and CD4 2 cDC loaded with graded doses of the MHC class II-restricted OVA peptide induced a mixed cytokine response in OT-II CD4 + T lymphocytes characterized by equivalent levels of secreted IFN-c and IL-13, whatever the time point analysed. Similarly, loading of CD4 + and CD4 2 cDC with whole OVA resulted in an equivalent ...
Context 4
... doses of the MHC class II-restricted OVA peptide induced a mixed cytokine response in OT-II CD4 + T lymphocytes characterized by equivalent levels of secreted IFN-c and IL-13, whatever the time point analysed. Similarly, loading of CD4 + and CD4 2 cDC with whole OVA resulted in an equivalent release of IFN-c and IL-13 by OT-II CD4 + T lymphocytes (Fig. 1C). IL-4 and IL-5 were undetectable in all culture supernatants. Thus, CD4 + and CD4 2 cDC pulsed with OVA peptide or whole OVA protein equally prime CD4 + T lymphocytes to differentiate into a mixed T cell ...
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Temporal down-regulation of the CD8 co-receptor after receiving positive-selection signals has been proposed to serve as an important determinant to segregate helper versus cytotoxic lineages by generating differences in the duration of TCR signaling between MHC-I and MHC-II selected thymocytes. By contrast, little is known about whether CD8 also m...
Citations
... Analyses of the spleens of control and CD4 SHP2mut mice revealed increased cell numbers but rather comparable frequencies of T cells and T cell subsets ( Figure 1B). Since CD4 is not exclusively expressed in T cells but also in a subset of macrophages and DCs (33)(34)(35), the question remained whether the observed expansion is T cell-specific or an indirect effect of hyper-proliferating myeloid cells. To exclude effects raised by macrophages and other antigen presenting cells, we further crossed the conditional SHP2 D61Y floxed mice to pre-T cell receptor a (pTa) mice. ...
Upon antigen recognition by the T cell receptor (TCR), a complex signaling network orchestrated by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) regulates the transmission of the extracellular signal to the nucleus. The role of the PTPs Src-homology 2 (SH2) domain-containing phosphatase 1 (SHP1, Ptpn6) and Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2, Ptpn11) have been studied in various cell types including T cells. Whereas SHP1 acts as an essential negative regulator of the proximal steps in T cell signalling, the role of SHP2 in T cell activation is still a matter of debate. Here, we analyzed the role of the constitutively active SHP2-D61Y-mutant in T cell activation using knock-in mice expressing the mutant form Ptpn11D61Y in T cells. We observed reduced numbers of CD8⁺ and increased numbers of CD4⁺ T cells in the bone marrow and spleen of young and aged SHP2-D61Y-mutant mice as well as in Influenza A Virus (IAV)-infected mice compared to controls. In addition, we found elevated frequencies of effector memory CD8⁺ T cells and an upregulation of the programmed cell death protein 1 (PD-1)-receptor on both CD4⁺ and CD8⁺ T cells. Functional analysis of SHP2-D61Y-mutated T cells revealed an induction of late apoptosis/necrosis, a reduced proliferation and altered signaling upon TCR stimulation. However, the ability of D61Y-mutant mice to clear viral infection was not affected. In conclusion, our data indicate an important regulatory role of SHP2 in T cell function, where the effect is determined by the kinetics of SHP2 phosphatase activity and differs in the presence of the permanently active and the temporally regulated phosphatase. Due to interaction of SHP2 with the PD-1-receptor targeting the protein-tyrosine phosphatase might be a valuable tool to enhance T cell activities in immunotherapy.
... Furthermore, we observed that the functional diversity of DCs at day 7 is characterized by three functional states (Fig. 5D) and could reflect differential DCs maturation during the inflammatory response, as reported in previous reports [37]. In addition, the functional state CS3 is the most different with the expression of Cd86, Cd4, and especially Ccl22, suggesting this state to be actively recruiting other cells, such as invariant NKT or regulatory T cells, in response to the infection [38][39][40][41]. ...
Immunomodulation strategies are crucial for several biomedical applications. However, the immune system is highly heterogeneous and its functional responses to infections remains elusive. Indeed, the characterization of immune response particularities to different pathogens is needed to identify immunomodulatory candidates. To address this issue, we compiled a comprehensive map of functional immune cell states of mouse in response to 12 pathogens. To create this atlas, we developed a single-cell-based computational method that partitions heterogeneous cell types into functionally distinct states and simultaneously identifies modules of functionally relevant genes characterizing them. We identified 295 functional states using 114 datasets of six immune cell types, creating a Catalogus Immune Muris. As a result, we found common as well as pathogen-specific functional states and experimentally characterized the function of an unknown macrophage cell state that modulates the response to Salmonella Typhimurium infection. Thus, we expect our Catalogus Immune Muris to be an important resource for studies aiming at discovering new immunomodulatory candidates.
... Besides its role in T cell activation, the CD4 receptor is suggested to be involved in peripheral T cell differentiation towards the T helper 2 subset and in the chemotactic response of CD4 + T cells towards interleukin (IL)-16 (10,11). Additionally, different functions are attributed to the CD4 receptor in other types of immune cells including natural killer and dendritic cells (12,13). The important role of the CD4 receptor in the immune system has been further demonstrated by the in vitro and in vivo immunosuppressive potential of non-depleting anti-CD4 monoclonal antibodies (14)(15)(16). ...
The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4⁺ and CD8⁺ T cells but was, surprisingly, most prominent in the CD8⁺ T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8⁺ T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders.
... The heterogeneous cDC2 population can be further subdivided according to the differential expression of CD4 and the endothelial cell-selective adhesion molecule (ESAM), although this does not result in clearly defined homogenous populations (48), which makes it difficult to determine individual immune-modulatory capacities. Due to their similarities in phenotype and gene expression profiles, both CD4 + CD8 − cDC2 (which largely co-express ESAM) and CD4 − CD8 − doublenegative cDC2 are often collectively referred to as CD8 − cDC2 (19,(49)(50)(51)(52), however, according to recent studies these two subsets appear different (44,53). For example, ESAM low cDC2 General Phenotype exhibit a more myeloid signature with Csf-1R, Csf3R, CCR2 and Lysozyme expression, suggesting that they are related to monocytes rather than to cDC. ...
Dendritic cells (DC) fulfill an essential sentinel function within the immune system, acting at the interface of innate and adaptive immunity. The DC family, both in mouse and man, shows high functional heterogeneity in order to orchestrate immune responses toward the immense variety of pathogens and other immunological threats. In this review, we focus on the Langerin⁺CD8⁺ DC subpopulation in the spleen. Langerin⁺CD8⁺ DC exhibit a high ability to take up apoptotic/dying cells, and therefore they are essential to prime and shape CD8⁺ T cell responses. Next to the induction of immunity toward blood-borne pathogens, i.e., viruses, these DC are important for the regulation of tolerance toward cell-associated self-antigens. The ontogeny and differentiation pathways of CD8⁺CD103⁺ DC should be further explored to better understand the immunological role of these cells as a prerequisite of their therapeutic application.
... In active natural killer cells, the CD4 receptor plays a role in chemotaxis towards IL-16 and in cytokine production of interferon-γ and tumor necrosis factor-α [72]. In spleenresident dendritic cells, CD4 is involved in the priming of invariant natural killer T cells[73]. ...
... Dendritic cells, especially CD8α + DCs, which are a major producer of IL-12 (71), play a critical role in glycolipid agonist presentation and NKT cell activation (72)(73)(74)(75)(76)(77)(78). Activated NKT cells reciprocate by activating the interacting DCs. ...
Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective.
... A key feature of NKT-cell activation by GalCer is cross-talk with other cells of the immune system. DCs, which are critical for the activation of naïve conventional T cells, are essential for glycolipid antigen presentation and NKT-cell activation (Arora et al., 2014;Bai et al., 2012;Bezbradica et al., 2005;Bialecki et al., 2011;Fujii et al., 2002;Macho-Fernandez et al., 2014). DCs are the immediate target of this activation, that is, NKT-DC cross-talk results in the stimulation and maturation of DC through activated NKT-cell-derived IFN-and CD154 (CD40 ligand on NKT cells)-CD40 (on DC) interaction (Kitamura et al., 1999;Vincent et al., 2002). ...
Natural killer T (NKT) cells that express the semi‐invariant T‐cell receptor are innate‐like lymphocytes whose functions are controlled by self and foreign glycolipid ligands. Such ligands are presented by the antigen‐presenting, MHC class I‐like molecule CD1d, which belongs to a family of lipid antigen‐presenting molecules collectively called CD1. Activation of NKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self‐antigens. The nature of CD1d‐restricted ligands, the manners in which they are recognised and the unique effector functions of NKT cells suggest an immunoregulatory role for this T‐cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine responses to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This article summarises our current understanding of CD1d‐restricted NKT cell biology and how these innate‐like lymphocytes control inflammation.
Key Concepts
CD1d molecules belong to a family of lipid antigen‐presenting molecules collectively called CD1.
CD1d molecules resemble peptide antigen‐presenting MHC class I molecules.
CD1d molecules restrict the specificity and functions of Natural killer T (NKT) cells.
NKT cells recognise self‐ and nonself‐lipid ligands.
Antigen recognition quickly activates NKT cells, which respond immediately by releasing proinflammatory and immunoregulatory cytokines and chemokines.
Activated NKT cells communicate with cells of the innate and adaptive immune systems by cell–cell interactions and/or via soluble mediators.
Such communications allow NKT cells to control immune responses to microbial pathogens and certain cancers.
NKT‐cell activation has beneficial and, sometimes, adverse effects on certain autoimmune and metabolic disorders.
NKT cells are targets for vaccine adjuvants and immunotherapies.
... Previous reports show the functional difference between CD4 + and CD4 2 CD8a 2 cDCs (33, 34). CD8a 2 cDCs activate CD4 + or CD8a + T cells, but the ability is not dependent on CD4 + expression on cCDs (35). In contrast, CD4 2 cDCs activate iNKT cells more effectively than CD4 + cDCs (35). ...
... CD8a 2 cDCs activate CD4 + or CD8a + T cells, but the ability is not dependent on CD4 + expression on cCDs (35). In contrast, CD4 2 cDCs activate iNKT cells more effectively than CD4 + cDCs (35). iNKT cells are localized in the marginal zone and known to activate splenic B cells (36,37). ...
TLR7 recognizes pathogen-derived and self-derived RNA, and thus a regulatory system for control of the TLR7 response is required to avoid excessive activation. Unc93 homolog B1 (Unc93B1) is a regulator of TLR7 that controls the TLR7 response by transporting TLR7 from the endoplasmic reticulum to endolysosomes. We have previously shown that a D34A mutation in Unc93B1 induces hyperactivation of TLR7, and that Unc93b1(D34A/D34A) mice (D34A mice) have systemic inflammation spontaneously. In this study, we examined the roles of inflammatory cytokines such as IFN-γ, IL-17A, and type I IFNs to understand the mechanism underlying the phenotype in D34A mice. mRNAs for IFN-γ and IL-I7A in CD4(+) T cells increased, but inflammatory phenotype manifesting as thrombocytopenia and splenomegaly was still observed in Ifng(-/-) or Il17a(-/-) D34A mice. In contrast to T cell-derived cytokines, Ifnar1(-/-) D34A mice showed an ameliorated phenotype with lower expression of TLR7 in B cells and conventional dendritic cells (cDCs). The amount of TLR7 decreased in B cells from Ifnar1(-/-) D34A mice, but the percentage of TLR7(+) cells decreased among CD8α(-) cDCs. In conclusion, type I IFNs maintain expression of TLR7 in B cells and cDCs in different ways; total amount of TLR7 is kept in B cells and TLR7(+) population is retained among cDCs. Our results suggested that these TLR7-expressing cells are activated initially and influence TLR7-dependent systemic inflammation.
... A key feature of NKT-cell activation by GalCer is cross-talk with other cells of the immune system. DCs, which are critical for the activation of naïve conventional T cells, are essential for glycolipid antigen presentation and NKT-cell activation (Arora et al., 2014;Bai et al., 2012;Bezbradica et al., 2005;Bialecki et al., 2011;Fujii et al., 2002;Macho-Fernandez et al., 2014). DCs are the immediate target of this activation, that is, NKT-DC cross-talk results in the stimulation and maturation of DC through activated NKT-cell-derived IFN-and CD154 (CD40 ligand on NKT cells)-CD40 (on DC) interaction (Kitamura et al., 1999;Vincent et al., 2002). ...
Natural killer T (NKT) cells that express the semi-invariant T cell receptor are innate-like lymphocytes whose functions are regulated by self and foreign glycolipid ligands. Such ligands are presented by the antigen-presenting, MHC class I-like molecule CD1d, which belongs to a family of lipid antigen-presenting molecules collectively called CD1. Activation of NKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers, and self-antigens. The nature of CD1d-restricted ligands, the manners in which they are recognised, and the unique effector functions of NKT cells suggest an immunoregulatory role for this T cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine responses to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarises our current understanding of CD1d-restricted NKT cell biology and how these innate-like lymphocytes control inflammation.
... Interestingly, DCs residing in or migrating into various organs seem to be distinct and potentially be classified into subsets according to surface marker molecules and functions [3,4]. These DC subsets have been suggested to have distinct roles in the initiation of different types of immune responses [3,5,6]. ...
Dendritic cell (DC) subsets in the skin and draining lymph nodes (LNs) are likely to elicit distinct immune response types. In skin and skin-draining LNs, a dermal DC subset expressing macrophage galactose-type C-type lectin 2 (MGL2/CD301b) was found distinct from migratory Langerhans cells (LCs) or CD103(+) dermal DCs (dDCs). Lower expression levels of Th1-promoting and/or cross-presentation-related molecules were suggested by the transcriptome analysis and verified by the quantitative real-time PCR analysis in MGL2(+) dDCs than in CD103(+) dDCs. Transfer of MGL2(+) dDCs but not CD103(+) dDCs from FITC-sensitized mice induced a Th2-type immune response in vivo in a model of contact hypersensitivity. Targeting MGL2(+) dDCs with a rat monoclonal antibody against MGL2 efficiently induced a humoral immune response with Th2-type properties, as determined by the antibody subclass. We propose that the properties of MGL2(+) dDCs, are complementary to those of CD103(+) dDCs and skew the immune response toward a Th2-type response.
