The confirmation of sex differences in immune responses, the immune responses mediated by T cells well entrenched, is bivalent. While women have a more robust response to pathogens, most of the autoimmune disease patients with diseases associated with dysregulated T cells are female.
In the School of Veterinary Medicine, Montserrat Anguera and her lab have been exploring this and other mechanisms related to these processes and the role of the X chromosome in them.
In some female mammals, genes are controlled by a process known as X chromosome inactivation in which one of the two X chromosomes associations is shut down. It is sustained by Xist RNA, a long noncoding RNA molecule, transcribed from the neocortex of the inactive X chromosome.
The earlier study from the Anguera Lab established that unstimulated T cells did not have Xist RNA and other alterations on the inactive X chromosome, although upon stimulating T cells with an antigen, Xist RNA and epigenetic marks reappeared.
She and collaborators wondered: This raises the question of what triggers are required for the Xist RNA to regain? And how much of the inactive X chromosome is actually silenced in T cells?
Now the researchers have discovered the answers. The regulation of XCI is reliant with the transcription factor that is nuclear factor kappa B (NF-κB) and some T cell-specific X-linked genes are able to escape this process.
To our knowledge, this is the first paper showing that in maintenance of X chromosome inactivation in T cells in female mice different NF-kB signalling pathways, all of them important in T cells development, embryonic development and so on, are involved. These findings are from a publication of Science Immunology which is the AAAS journal of Immunology.
Toothacre elaborates CUT & RUN as a means for identifying the location at which a given protein interacts with DNA, and here, investigators wanted to look at heterochromatic histone modifications associated with the inactivated X chromosome. These two papers showed they were able to knock in a reporter gene where they could isolate and sequence the DNA to see where this mark is enriched on the X chromosome and how stimulation changes enrichment.
They collaborated with Michael May from Penn Vet who studies NF-κB signalling pathways, and with Neil Romberg from Children’s Hospital of Philadelphia who watched a presentation Forsyth delivered and asked her if she researched patients with NF-κB deficiencies.
Forsyth said that Romberg had residual cells of a patient with combined variable immunodeficiency disease, which is sometimes due to NF-κB mutations, from a previous study, and obtained more vials of blood samples from other collaborators for this study.
I think it just really emphasises the fact that interdisciplinary collaboration and being across the Penn community is so valuable and having these amazing people that we can work with to truly drive our science and take it to this level,” Anguera says.
Reference: Moser E. An integral T cell pathway has implications for understanding sex-based immune response
