Th2 cells: orchestrating barrier immunity.
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Animals↗
Biomedical subjects
Jane L Grogan
Publications and source records attributed to Jane L Grogan.
Basal chromatin modification at the IL-4 gene in helper T cells.
Chromatin immunoprecipitations in naive CD4, but not CD8, T cells, demonstrated association of the IL-4 promoter with acetylated histone. Histone modifications and rapid IL-4 transcription were absent in conserved noncoding sequence 1 (CNS-1)(-/-) cells lacking an 8-kb-distant enhancer in the IL-4/IL-13 intergenic region, but also in CD4(-/-) and Itk(-/-) cells, which have similar Th2 deficiencies. Histones associated with the IL-13 promoter were not similarly acetylated in naive T cells, but became acetylated in differentiated Th2 cells. Conversely, Th1 differentiation induced histone methylation at the type 2 cytokine locus. Like CD4(-/-) and Itk(-/-) mice, CNS-1(-/-) BALB/c mice were highly resistant to the Th2-inducing protozoan, Leishmania major. CNS-1 deficiency led to failure of IL-4 gene repositioning to heterochromatin after Th1 polarization, possibly related to the presence of reiterative Ikaros binding sites in the intergenic element. Hyperacetylation of nonexpressed genes may serve to mark lineage-specific loci for rapid expression and further modification.
Animals↗
CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.
The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4-deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.
Abatacept↗
T helper cell differentiation: on again, off again.
Recent studies raise the possibility that T helper (Th) polarization may be attributable to generalized activation and regulated silencing rather than regulated activation of target cytokine genes. The binding of transcription factors GATA-3 or T-bet to specific enhancers does recruit transcription factors such as NFAT-1 to IL-4 or IFNgamma promoters, respectively; however, GATA-3 also intrinsically suppresses T-bet and vice versa. Silencing of GATA-3/T-bet, which is influenced by factors such as cytokines, is associated with irreversible Th polarization. For the first few divisions (perhaps reflecting the situation in lymph nodes), naive Th cells retain pluripotency; after further cell divisions (perhaps under the influence of an inflammatory cytokine milieu) they may become polarized appropriately to respond to the specific environment.
Animals↗
Human IgE response to the Schistosoma haematobium 22.6 kDa antigen.
In Schistosoma mansoni and S. japonicum infection, the 22.6 kDa tegumental antigens Sm22.6 and Sj22.6 are principal targets for the human IgE response, and levels of IgE to Sm22.6 have been correlated with resistance to re-infection after chemotherapy. S. haematobium is arguably a more important species in terms of human infection, and in this report we describe for the first time the molecular characterization of a cDNA from S. haematobium (Sh22.6) that is closely homologous to Sm22.6 and Sj22.6. As a member of the tegument-associated antigen family, Sh22.6 possesses EF-hand domains and regions homologous to the dynein light chain domains. We have expressed recombinant Sh22.6 and studied the IgE responses to the antigen in a group of 99 infected individuals (68 children and 31 adults) from an endemic area of Gabon who donated blood before and 5 weeks after praziquantel treatment. IgE to Sh22.6 was detected by ELISA in 18 subjects (18%), and in the majority of responders levels rose between pre- and post-treatment. Interestingly, the proportion of adults expressing IgE to Sh22.6 was 35.5%, significantly higher than the 10.3% seen in children. IgE from at least 10 of the 18 ELISA responders recognized Sh22.6 on Western blots of adult worm extract and recombinant antigen. These results demonstrate that like related molecules in other species, Sh22.6 is a target for the human IgE response. The data also indicate that changes in the IgE response occur with age or with progressive exposure to key antigens.
Adolescent↗