<i>In vivo</i>
            studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation

Panhuys, Nicholas J. Van; Tang, Shiau Choot; Prout, Melanie; Camberis, Mali; Scarlett, Debbie; Roberts, Joanna M.; Hu‐Li, Jane; Paul, William E.; Gros, Graham Le

doi:10.1073/pnas.0806372105

Cited by 111 publications

(167 citation statements)

References 36 publications

(40 reference statements)

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“…The small population of Lat Y136F Stat6 Ϫ/Ϫ Th2 effectors that develop in parallel to the dominant Th1 cells might correspond to cells in which the levels of T-bet were lower than the threshold required for inhibiting basal levels of GATA-3 and Th2 differentiation. Similar to the situation observed in in Lat Y136F Stat6 Ϫ/Ϫ mice, it has been recently reported that in some situations Th2 differentiation occurs in a manner independent of STAT6 (32)(33)(34). The Th1 and CD8 T cells that dominate the lymphoid compartment of Lat Y136F Stat6 Ϫ/Ϫ mice and are capable of producing IFN-␥ were unable to suppress the development of these few Th2 cells.…”

Section: Stat6mentioning

confidence: 48%

“…IL-4/STAT6 signaling is generally considered to be essential for the production of IgE (13,34,36 (9,10,12). Using CD8 T cells purified from 5 to 6-wk-old Lat Y136F Stat6 Ϫ/Ϫ mice, a time-point when the disease is largely established, we showed that, upon infusion into CD3-deficient hosts, those cells expanded independently of the presence of Lat Y136F Stat6 Ϫ/Ϫ CD4 T cells (data not shown).…”

Section: Y136fmentioning

confidence: 91%

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STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells

Archambaud

Sansoni

Mingueneau

et al. 2009

The Journal of Immunology

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Mutant mice in which tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (LatY136F mice) develop a lymphoproliferative disorder involving polyclonal CD4 effector T cells that produce massive amounts of IL-4 and trigger severe Th2 inflammation. Naive CD4 T cells can themselves produce IL-4 and thereby initiate a self-reinforcing positive regulatory loop that involves the STAT6 transcription factor and leads to Th2 polarization. We determined the functional outcome that results when LatY136F T cells differentiate in the absence of such STAT6-dependent regulatory loop. The lack of STAT6 had no effect on the timing and magnitude of the lymphoproliferative disorder. However, in LatY136F mice deprived of STAT6, the expanding CD4 T cell population was dominated by Th1 effector cells that triggered B cell proliferation, elevated IgG2a and IgG2b levels as well as the production of autoantibodies. In contrast to LatY136F mice that showed no CD8 T cell expansion, the CD8 T cells present in LatY136F mice deprived of STAT6 massively expanded and acquired effector potential. Therefore, the lack of STAT6 is sufficient to convert the Th2 lymphoproliferative disorder that characterizes LatY136F mice into a lymphoproliferative disorder that is dominated by Th1 and CD8 effector T cells. The possibility to dispose of a pair of mice that differs by a single gene and develops in the absence of deliberate immunization large numbers of Th cells with almost reciprocal polarization should facilitate the identification of genes involved in the control of normal and pathological Th cell differentiation.

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Section: Stat6mentioning

confidence: 48%

Section: Y136fmentioning

confidence: 91%

STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells

Archambaud

Sansoni

Mingueneau

et al. 2009

The Journal of Immunology

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“…Interestingly, in certain situations, neither IL-4 nor STAT6 signaling is required for the induction or differentiation of Th2 cells within the lymph nodes, as demonstrated using green fluorescent protein reporter transgenic techniques, which showed that IL-4-producing Th2 cells can develop in IL-4R-and STAT6-deficient animals undergoing certain Th2-mediated helminth infections and allergic immune responses with equivalent magnitude and timing to their IL-4/STAT6 sufficient counterparts (Paul 2010;van Panhuys et al 2008). Nevertheless, these studies re-emphasize the importance of IL-4/STAT6 at mucosal sites and highlight the importance of IL-4/STAT6 in the induction of type 2 effector responses, including Th2 effector cell migration, eosinophil migration, and B cell IgE class switching (Harris et al 2002;Kaplan et al 1996;Kopf et al 1993).…”

Section: Il-4/stat6 Signaling In Vivomentioning

confidence: 99%

Cytokine Pathways in Allergic Disease

et al. 2012

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Cytokines are critical in allergic intercellular communication networks, and they contribute to disease pathology through the recruitment and activation of pro-inflammatory leukocytes and in chronic disease to pro-fibrotic/remodeling events. Th2 cytokines predominate primarily in mild to moderate allergic asthma, although clinical trials with inhibitors of IL-4 and IL-5 have not provided the robust efficacy observed in animal models of allergy. These results not only highlight the complexity of allergic disease, but they also point to the importance of other cytokine networks in driving pathology. The heterogeneous nature of the disease is emphasized by the fact that the Th2/Th1/Th17 cytokine balance can be influenced by the initiating allergic trigger. For example, the house dust mite allergen Der p 2 mimics the activity of MD-2 by presenting lipopolysaccharide to Toll-like receptor-4 for the activation of inflammatory genes including innate-type cytokines. Here we discuss the functions of the novel cytokine players, thymic stromal lymphopoetin (TSLP), IL-33, IL-25, and IL-9 and delineate nonredundant roles for IL-4 and IL-13 in allergic disease. Persistent efforts in the characterization of these and other cytokine networks will be essential for understanding the complex pathogenic mechanisms that underpin allergic disease and for guiding targeted therapeutic interventions.

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“…N. brasiliensis elicits strong Th2 immune responses in lung and gut (29), and administration of nonviable N. brasiliensis L3 larvae (Nb) into ear skin triggers a strong and highly polarized Th2 response in the ear-dLN (30). In this paper, we combine the powerful Nb model of Th2 immune response with a highly sensitive readout of IL-4 production in vivo to investigate the induction of Th2 responses by DC.…”

mentioning

confidence: 99%

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Connor

Tang

Camberis

et al. 2014

The Journal of Immunology

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Dendritic cells (DC) are critical for the initiation of immune responses; however, their role in priming IL-4–producing Th2 cells in vivo is not fully understood. We used a model of intradermal injection with fluorescent-labeled, nonviable larvae from the helminth parasite nonviable Nippostrongylus brasiliensis L3 larvae (Nb), a strong inducer of Th2 responses, together with IL-4–GFP reporter mice that enable a sensitive detection of IL-4 production to examine the contribution of DC to the priming of IL-4–producing CD4+ T cells in vivo. We found that parasite material is taken up by two distinct DC populations in draining lymph nodes: a mostly CD11cintMHC class II (MHCII)hiCD11b+Ly6C− dermal DC population and a CD11chiMHCIIintCD11b+Ly6C+ monocyte-derived DC population. After Nb treatment, these two DC populations appeared in the draining lymph nodes in comparable numbers and with similar kinetics; however, treatment with pertussis toxin blocked the migration of dermal DC and the priming of IL-4–producing T cells, but only partially affected monocyte-derived DC numbers. In line with this observation, transfer of OVA-loaded CD11cintMHCIIhi DC from Nb-treated mice into naive hosts could sensitize OVA-specific CD4+ T cells to IL-4 production, whereas transfer of CD11cintMHCIIhi DC from naive mice, or CD11chiMHCIIint DC from Nb-treated or naive mice, induced CD4+ T cell expansion but no IL-4 production. Phenotypic analysis of Nb-loaded CD11cintMHCIIhi DC revealed expression of programmed death ligand 2, CD301b, IFN regulatory factor 4, and moderate upregulation of OX40 ligand. However, thymic stromal lymphopoietin and OX40 ligand were not required for Th2 priming. Thus, our data suggest that appropriate stimuli can induce DC to express the unique signals sufficient to direct CD4+ T cells to Th2 differentiation.

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In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation

Cited by 111 publications

References 36 publications

STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells

STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells

Cytokine Pathways in Allergic Disease

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

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