Follicular Helper T Cells and B Cell Maturation in Patients with 22q11.2 Deletion Syndrome and Recurrent Infections

22q11.2 Deletion Syndrome has been primarily described as a disorder of T cell production secondary to thymic hypoplasia. However, there is great complexity in the clinical picture with infections, autoimmunity, and inflammation occurring. Emerging evidence suggests that qualitative T cell dysfunction occurs, and the goal of this study was to utilize single-cell RNA-seq to better define altered gene expression patterns to inform on the mechanisms associated with recurrent infections.

We utilized single-cell RNA-seq to define distinct populations in 22q11.2 Deletion Syndrome (N = 13) and controls (N = 11) as well as within a subcohort of patients with 22q11.2 Deletion Syndrome and recurrent infections.

When we analyzed differentially expressed genes, we identified a signature of type I interferons across all cell types. Within the T cell compartment, and particularly within the follicular helper T cells, we identified a senescence signature. The alterations found in T cells were most substantial in the patients with recurrent infection.

While T cell numbers can often normalize in patients with 22q11.2 Deletion Syndrome, our data indicate significantly altered function as defined by differentially expressed genes and aligned with what is known about T cell senescence. The effect was greatest in the patients with recurrent infection. This would be expected to impact T cell function and may account for ongoing symptoms, reduced B cell maturation, and possibly the risk of immune dysregulation.