Abstract Text: Many people newly diagnosed with Type 1 Diabetes (T1D) experience a partial remission that can last from a few weeks to two years. Length of remission (LoR) is associated with residual beta-cell function and a reduced risk of secondary complications. CD4+CD25+CD127hi (127-hi) cells are a novel T cell population identified by our group, whose frequency at diagnosis correlates with LoR. Although 127-hi cells are a mixed population of naïve and memory anti-inflammatory Th2 and pro-inflammatory Th1 cells, compared to other CD4 subsets they have an enhanced Th2 profile. These data have led us to hypothesize that 127-hi Th2 cells actively prolong partial remission. To this end we have quantified cell subsets within the 127-hi cell population from the pediatric ExTEND study and found that it is the frequency of Th2 effector memory (EM) cells drives the correlation with LoR. Paired scRNAseq with TCR sequencing of 127-hi cells has identified unique Th2 cell clusters within this compartment that clonally expand. Th2 clusters are identified by classical (GATA3) and non-classical (CRTH2) Th2 genes, compared to other memory CD4 T cells. A typical Th2 cluster shows upregulation IL17RB, IL9R, TNFRSF11A, CCR4, IL4R, GATA3-AS1 along with downregulation of Th1-like genes GZMK, GZMA, IFNG-AS1, EOMES. Interestingly, these Th2 clusters are absent in other memory CD4 subsets. Our combined data show a link between LoR and the clonal expansion of 127-hi Th2 EM. Additional analysis will reveal whether the patients that experience 127-hi Th2 EM clonal expansion have a longer partial remission.
