ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells

Abstract

T helper (T H ) cell polarization during priming is modulated by a number of signals, but whether polarization to a given phenotype also influences recall responses of memory T H cells is relatively unknown. Here we show that miR-181a is selectively induced in both human and mouse naive T cells differentiating into the T H 17, but not T H 1 or T H 2 subset. In human memory T H 17 cells, miR-181a regulates responses to cognate antigens through modulation of ERK phosphorylation. By enhancing the signalling cascade from the T-cell receptor, such molecular network reduces the threshold of T H 17 cell activation. Moreover, at a late time point, the same network induces a self-regulatory mechanism dependent on ID3, a negative regulator of transcription factors that control RORC expression, thus modulating T H 17 activity. Our results demonstrate that the phenotype acquired by T H cells during priming contributes to their threshold of activation to secondary antigenic stimulations, thus influencing memory responses.

Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance

“…However the biological consequence and relevance of lowered Erk activity upon TCR reactivation leading to lowered FasL protein and reduced caspase activity in Th17 cells suggest direct proof of principle for their AICD resistance and higher incidence in inflammatory diseases including psoriasis, RA, inflammatory bowel disease and multiple sclerosis [36–39]. Evidence from other groups and ours (unpublished data) suggest that lowered Erk activity post TCR activation tends to favor Th17 propagation [40, 41] and Erk2 enhancement sensitizing Th17 cells to TCR AICD has major consequence attached.…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…127,131 The expression of miR-181a is lower in naive T-helper cells as compared to thymocytes, and it further declines upon TCR activation and cell differentiation. 128 Since TCR signal strength is known to determine Tfh cell differentiation 132 and a recent study indicated that the miR-181a target DUSP6 inhibits Tfh cell differentiation, 133 it is possible that miR-181a may also regulate Tfh cells. 127,129 An additional study showed that miR-181a is highly expressed in Th17 cells and that it regulates the TCR signaling threshold specifically in Th17 cells as compared to Th1 or Th2 cells.…”

“…126 Several studies showed that miR-181a regulates the TCR signaling threshold of T-helper cells. [127][128][129][130] miR-181a is highly expressed in thymocytes, where it facilitates positive selection. 127,131 The expression of miR-181a is lower in naive T-helper cells as compared to thymocytes, and it further declines upon TCR activation and cell differentiation.…”

“…127,129 An additional study showed that miR-181a is highly expressed in Th17 cells and that it regulates the TCR signaling threshold specifically in Th17 cells as compared to Th1 or Th2 cells. 128 Since TCR signal strength is known to determine Tfh cell differentiation 132 and a recent study indicated that the miR-181a target DUSP6 inhibits Tfh cell differentiation, 133 it is possible that miR-181a may also regulate Tfh cells.…”

The Inescapable Influence of Noncoding RNAs in Cancer

“…Dr. Silvia Monticelli (Institute for Research in Biomedicine, Bellinzona, Switzerland) discussed how miRNAs play an important role in affecting the ability of naïve CD4 T cells to differentiate into a number of different memory and effector subsets. Specifically, she showed that miR-181a was selectively induced in both human and mouse naïve T cells differentiating into the T H 17 subset(13). In T H 17 cells, miR-181a also regulated responses to cognate antigens through modulation of ERK phosphorylation.…”