MicroRNA miR-181-A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

Abstract

The selection of T cells during intra-thymic d evelopment is crucial to obtain a functional and simultaneously not self-reactive peripheral T cell repertoire. However, selection is a complex process dependent on T cell receptor (TCR) thresholds that remain incompletely understood. In peripheral T cells, activation, clonal expansion, and contraction of the active T cell pool, as well as other processes depend on TCR signal strength. Members of the microRNA (miRNA) miR-181 family have been shown to be dynamically regulated during T cell development as well as dependent on the activation stage of T cells. Indeed, it has been shown that expression of miR-181a leads to the downregulation of multiple phosphatases, implicating miR-181a as ''rheostat'' of TCR signaling. Consistently, genetic models have revealed an essential role of miR-181a/b-1 for the generation of unconventional T cells as well as a function in tuning TCR sensitivity in peripheral T cells during aging. Here, we review these broad roles of miR-181 family members in T cell function via modulating TCR signal strength.

Keywords: T cell receptor; miR-181; microRNA; selection; signaling; thymus; unconventional T cell.

Figure 1

Conventional and agonist selected T cells possess different affinity windows for positive selection. Conventional T cells require low to moderate TCR affinities to peptide: MHC to receive survival signals, whereas agonist selected T cells depend on relatively high affinities towards peptide: MHC to be positively selected.

Figure 2

Characteristics of the miR-181 family. (A) Mature sequences of murine miR-181a, b, c, and d. Seed sequences are marked in yellow, asterisks indicate the consensus bases of all four microRNAs. Colored boxes highlight differences between family members. (B) Dynamic expression profiles of miR-181a(/b-1) in T cells from thymus (left) and periphery (right). The shaded area in the thymus indicates the phase of thymic selection. (C) Schematic depiction of miR-181a targets in the TCR signaling cascade. Positive and negative signaling relationships are indicated by solid lines. miR-181a targets PTPN22, DUSP5/6, and SHP-2, which, in turn, regulate Lck and ZAP-70, Erk1/2 and negative costimulatory signals elicited by CTLA4, respectively. Additionally, an indirect effect of miR-181a on SHP-1 has been proposed (denoted by question mark and dotted arrow).

Figure 3

Hypothetical function of miR-181a/b-1 as rheostat for TCR signaling during selection. (A) How miR-181 affects conventional T cells: Due to their broad affinity window, the effect of the shift in TCR signal strength on selection is relatively small. (B) How miR-181 affects agonist selected T cells: Due to their high and narrow affinity window, the effect of the shift in TCR signal strength on selection is evident.