Immunology
Abstract
So far, there is very limited knowledge about the role of Eph kinases, the largest family of receptor tyrosine kinases, in the immune system. Here, using EphB6–/– mice, we demonstrated that in vitro and in vivo T cell responses such as lymphokine secretion, proliferation, and the development of delayed-type skin hypersensitivity and experimental autoimmune encephalitis in EphB6–/– mice were compromised. On the other hand, humoral immune responses, such as serum levels of different Ig isotypes and IgG response to tetanus toxoid, were normal in these mice. Mechanistically, we showed that EphB6 migrated to the aggregated TCRs and rafts after TCR activation. Further downstream, in the absence of EphB6, ZAP-70 activation, LAT phosphorylation, the association of PLCγ1 with SLP-76, and p44/42 MAPK activation were diminished. Thus, we have shown that EphB6 is pivotal in T cell function.
Authors
Hongyu Luo, Guang Yu, Johanne Tremblay, Jiangping Wu
Abstract
Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88–/– macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88–/– mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88–/– mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88–/– mice to control MTB infection.
Authors
Cecile M. Fremond, Vladimir Yeremeev, Delphine M. Nicolle, Muazzam Jacobs, Valerie F. Quesniaux, Bernhard Ryffel
Abstract
Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand α-galactosylceramide (α-GalCer) or the sphingosine-truncated α-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and γ interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli. The adjuvant activity of α-GalCer enhances both priming and boosting of CD8+ T cells to coadministered peptide or protein antigens, including a peptide encoding the clinically relevant, HLA-A2–restricted epitope of the human tumor antigen NY-ESO-1. Importantly, α-GalCer was used to induce CD8+ T cells to antigens delivered orally, despite the fact that this route of administration is normally associated with blunted responses. Only T cell responses induced in the presence of iNKT cell stimulation, whether by the i.v. or oral route, were capable of eradicating established tumors. Together these data highlight the therapeutic potential of iNKT cell ligands in vaccination strategies, particularly “heterologous prime-boost” strategies against tumors, and provide evidence that iNKT cell stimulation may be exploited in the development of oral vaccines.
Authors
Jonathan D. Silk, Ian F. Hermans, Uzi Gileadi, Tsung Wen Chong, Dawn Shepherd, Mariolina Salio, Bini Mathew, Richard R. Schmidt, Sarah Jane Lunt, Kaye J. Williams, Ian J. Stratford, Adrian L. Harris, Vincenzo Cerundolo
Abstract
The role of human NK cells in viral infections is poorly understood. We used a cytokine flow-cytometry assay to simultaneously investigate the IFN-γ response of NK and T lymphocytes to influenza A virus (fluA). When PBMCs from fluA-immune adult donors were incubated with fluA, IFN-γ was produced by both CD56dim and CD56bright subsets of NK cells, as well as by fluA-specific T cells. Purified NK cells did not produce IFN-γ in response to fluA, while depletion of T lymphocytes reduced to background levels the fluA-induced IFN-γ production by NK cells, which indicates that T cells are required for the IFN-γ response of NK cells. The fluA-induced IFN-γ production of NK cells was suppressed by anti–IL-2 Ab, while recombinant IL-2 replaced the helper function of T cells for IFN-γ production by NK cells. This indicates that IL-2 produced by fluA-specific T cells is involved in the T cell–dependent IFN-γ response of NK cells to fluA. Taken together, these results suggest that at an early stage of recurrent viral infection, NK-mediated innate immunity to the virus is enhanced by preexisting virus-specific T cells.
Authors
Xiao-Song He, Monia Draghi, Kutubuddin Mahmood, Tyson H. Holmes, George W. Kemble, Cornelia L. Dekker, Ann M. Arvin, Peter Parham, Harry B. Greenberg
Abstract
Hypomorphic mutations in the zinc finger domain of NF-κB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iε-Cε transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.
Authors
Ashish Jain, Chi A. Ma, Eduardo Lopez-Granados, Gary Means, William Brady, Jordan S. Orange, Shuying Liu, Steven Holland, Jonathan M.J. Derry
Abstract
IL-1 receptor antagonist–deficient (IL-1Ra–/–) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell–deficient IL-1Ra–/– mice did not develop arthritis, and transfer of IL-1Ra–/– T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-α deficiency. We found that TNF-α induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-α plays an important role in activating T cells through induction of OX40.
Authors
Reiko Horai, Akiko Nakajima, Katsuyoshi Habiro, Motoko Kotani, Susumu Nakae, Taizo Matsuki, Aya Nambu, Shinobu Saijo, Hayato Kotaki, Katsuko Sudo, Akihiko Okahara, Hidetoshi Tanioka, Toshimi Ikuse, Naoto Ishii, Pamela L. Schwartzberg, Ryo Abe, Yoichiro Iwakura
Abstract
Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane–enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell–mediated cytotoxicity and specific ligand recognition by cell surface–activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell–activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell–activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.
Authors
Jacob Hanna, Tsufit Gonen-Gross, Jonathan Fitchett, Tony Rowe, Mark Daniels, Tal I. Arnon, Roi Gazit, Aviva Joseph, Karoline W. Schjetne, Alexander Steinle, Angel Porgador, Dror Mevorach, Debra Goldman-Wohl, Simcha Yagel, Michael J. LaBarre, Jane H. Buckner, Ofer Mandelboim
Abstract
How Tregs migrate to GCs, and whether they regulate the helper activity of the T cells in GCs (GC-Th cells) remains poorly understood. We found a T cell subset in human tonsils that displays potent suppressive activities toward GC-Th cell–dependent B cell responses. These Tregs with the surface phenotype of CD4+CD25+CD69– migrate well to CCL19, a chemokine expressed in the T cell zone, but poorly to CXCL13, a chemokine expressed in the B cell zone. This migration toward the T cell–rich zone rapidly changes to trafficking toward B cell follicles upon T cell activation. This change in chemotactic behavior upon activation of T cells is consistent with their switch in the expression of the 2 chemokine receptors CXCR5 and CCR7. CD4+CD25+CD69– Tregs suppress GC-Th cells and GC-Th cell–induced B cell responses such as Ig production, survival, and expression of activation-induced cytosine deaminase. Our results have identified a subset of Tregs that is physiologically relevant to GC-Th cell–dependent B cell responses and a potential regulation mechanism for the trafficking of these Tregs to GCs.
Authors
Hyung W. Lim, Peter Hillsamer, Chang H. Kim
Abstract
Proteinase-activated receptor–1 (PAR1), a G protein–coupled receptor activated by thrombin, is highly expressed in different cell types of the gastrointestinal tract. The activity of thrombin and of other proteinases is significantly increased in the colon of inflammatory bowel disease (IBD) patients. Since PAR1 activation in tissues other than the gut provoked inflammation, we hypothesized that PAR1 activation in the colon is involved in the pathogenesis of IBD. Here, we demonstrate that PAR1 is overexpressed in the colon of IBD patients. In mice, intracolonic administration of PAR1 agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. This PAR1 activation–induced inflammation was dependent on B and T lymphocytes. Moreover, PAR1 activation exacerbated and prolonged inflammation in a mouse model of IBD induced by the intracolonic administration of trinitrobenzene sulfonic acid (TNBS), while PAR1 antagonism significantly decreased the mortality and severity of colonic inflammation induced by TNBS and dextran sodium sulfate. In these 2 models, colitis development was strongly attenuated by PAR1 deficiency. Taken together, these results imply an important role for PAR1 in the pathogenesis of experimental colitis, supporting the notion that PAR1 inhibition may be beneficial in the context of IBD and possibly in other chronic intestinal inflammatory disorders.
Authors
Nathalie Vergnolle, Laurie Cellars, Andrea Mencarelli, Giovanni Rizzo, Sunita Swaminathan, Paul Beck, Martin Steinhoff, Patricia Andrade-Gordon, Nigel W. Bunnett, Morley D. Hollenberg, John L. Wallace, Giuseppe Cirino, Stefano Fiorucci
Abstract
We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells. The condition was found in 5 patients and 2 fetuses from 3 consanguineous families. Linkage analysis performed on the 3 families revealed that the patients were carrying homozygous haplotypes within the 11q23 region, in which the genes encoding the γ, δ, and ε subunits of CD3 are located. Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene. The thymus from a CD3δ-deficient fetus was analyzed and revealed that T cell differentiation was blocked at entry into the double positive (CD4+CD8+) stage with the accumulation of intermediate CD4–single positive cells. This indicates that CD3δ plays an essential role in promoting progression of early thymocytes toward double-positive stage. Altogether, these findings extend the known molecular mechanisms underlying severe combined immunodeficiency to a new deficiency, i.e., CD3ε deficiency, and emphasize the essential roles played by the CD3ε and CD3δ subunits in human thymocyte development, since these subunits associate with both the pre-TCR and the TCR.
Authors
Geneviève de Saint Basile, Frédéric Geissmann, Elisabeth Flori, Béatrice Uring-Lambert, Claire Soudais, Marina Cavazzana-Calvo, Anne Durandy, Nada Jabado, Alain Fischer, Françoise Le Deist
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)