The molecular program of CD4⁺ regulatory and effector T cell expansion in vitro

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B734
Abstract ID: 5150

Presenting Author:
Alejandro Moro , Assistant scientist at Univ. of Miami Miller Sch. of Med.

Abstract:

Adoptive Treg therapy is being advanced to treat autoimmunity. To discern the molecular pathways underlying Treg expansion in vitro, we evaluated the chromatin landscape and gene expression profiles of Treg and Teff cells in response to TCR/CD28/IL-2 priming followed by IL-2 expansion over 12-days. Although initially similar over the first 6 days, Tregs showed somewhat higher STAT5 activation and   chromatin opening, leading to optimal expansion on day 6, which was 2-fold greater than Teff cells. After day 6, Tregs, but not Teff cells, showed substantial reduction in expansion. At day 9 and 12, more marked changes in gene expression and chromatin accessibility at promoter regions were seen between Treg and Teff cells. PCA revealed for RNAseq and ATACseq a clockwise movement, where the day 12 cells expressed a profile that reverts toward the input populations. Temporal integration of differentially expressed genes and chromatin accessibility revealed 6 patterns of responses, 4 of which were similar between Treg and Teff cells. The glycolytic activity in Treg and Teff cells during expansion until day 6 was similar but then they declined more rapidly in Tregs. Hence, these differences in gene accessibility and expression and glycolysis likely contribute to the more rapid decay in Treg expansion in response to IL-2. Thus, Tregs are programmed temporally for more limited expansion in vitro that may reflect a mechanism to finely tune Treg numbers to maintain homeostasis in vivo.