Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

This plot shows the frequency of different T cell subsets in trisomy 21 (blue) versus typicals (black). More differentiated subtypes are to the right.

This project took a deep dive into the T cell biology of people with Down syndrome. T cells are an important cell in the immune system. There are numerous types and subtypes of T cells, each with specific functions in the immune response. For example, “cytotoxic T cells” kill dangerous cells infected by virus or from tumors, “helper T cells” assist other parts of the immune system in their roles, and “regulatory T cells” prevent our immune responses from getting out of control.

Our scientists looked at T cells and other immune cells in a total of 274 blood samples from people enrolled in the Human Trisome Project. One of the first important findings was that while total numbers of T cells are unchanged in people with Down syndrome, the frequencies of certain types and subtypes are altered. Specifically, people with Down syndrome had more cytotoxic T cells and more regulatory T cells than typical controls.

Immunologists understand that T cells progress through a series of subtypes defined by their degree of differentiation and function. In this study, cytotoxic T cells from people with Down syndrome tended to have moved further along this progression – they were more differentiated and were hyperactivated, performing many tasks and functions (see figure above). Somewhat paradoxically, the cytotoxic T cells from people with Down syndrome also showed signs of senescence, meaning they were getting tired and burnt out. This is known to happen in the context of chronic immune stimulation and in autoimmune disorders.

The scientists also discovered that cytotoxic and helper T cells from people with Down syndrome are resistant to suppression by regulatory T cells. This means that the regulatory controls which normally keep the immune system in check are not as effective on the immune systems of people with Down syndrome. This dampening of regulation also can also happen in autoimmune disorders.

Our scientists also found that T cells from people with Down syndrome had higher levels of interferon signaling. In addition, the T cells responded to stimulation with interferon even stronger than the typical controls. The interferon signaling pathway is a branch of the immune system that normally gets turned on when the body is fighting off a virus, but people with Down syndrome have higher levels of interferon signaling naturally. This is most likely because four important genes in the interferon pathway are located on chromosome 21, and thus people with Down syndrome have an extra copy.

Overall, this research demonstrates specific changes in the T cell biology of people with Down syndrome which could help explain the different spectrum of diseases that people with Down syndrome experience, especially their increased risk for autoimmune disorders where T cells are involved in the pathogenesis, including Type I diabetes, celiac disease, alopecia areata, and some types of hypothyroidism. This research also adds to the mounting evidence that immune system dysregulation in people with Down syndrome is caused by the extra copy of the four interferon receptor genes located on chromosome 21, which leads to chronic interferon signaling, and thus chronic inflammation. This chronic inflammatory state could therefore be driving the T cell changes observed in this study and contributing to the increased incidence of autoimmune and inflammatory conditions in people with Down syndrome. 

Check out the full publication on PubMed.

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Paula Araya, Katherine A. Waugh, Kelly D. Sullivan, Nicolás G. Núñez, Emiliano Roselli, Keith P. Smith, Ross E. Granrath, Angela L. Rachubinski, Belinda Enriquez Estrada, Eric T. Butcher, Ross Minter, Kathryn D. Tuttle, Tullia C. Bruno, Mariana Maccioni, and Joaquín M. Espinosa. PNAS November 26, 2019; 116 (48) 24231-24241. PMID: 31699819. PMCID: PMC6883781.