miR‐21 sustains CD28 signalling and low‐affinity T‐cell responses at the expense of self‐tolerance

Abstract

Objective miR‐21 is highly expressed in iNKT and activated T cells, but its T‐cell autonomous functions are poorly defined. We sought to investigate the role of miR‐21 in the development and functions of T and iNKT cells, representing adaptive and innate‐like populations, respectively. Methods We studied mice with a conditional deletion of miR‐21 in all mature T lymphocytes. Results Thymic and peripheral T and iNKT compartments were normal in miR‐21 KO mice. Upon activation in vitro, miR‐21 depletion reduced T‐cell survival, TH17 polarisation and, remarkably, T‐ and iNKT cell ability to respond to low‐affinity antigens, without altering their response to high‐affinity ones. Mechanistically, miR‐21 sustained CD28‐dependent costimulation pathways required to lower the T‐cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T‐cell sensitivity to antigenic stimulation and survival. Upon immunisation with the low‐affinity self‐epitope MOG35–55, miR‐21 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T‐cell responses against high‐affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection. Conclusion The induction of T‐cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR‐21 sustains CD28 costimulation, decreasing the T‐cell activation threshold and increasing their sensitivity to antigenic stimulation and survival, broadening the immune surveillance range. This occurs at the cost of unleashing autoimmunity, resulting from the recognition of weak self‐antigens by autoreactive immune responses. Thus, miR‐21 fine‐tunes T‐cell response and self‐/non‐self‐discrimination.

Molecular and cellular control of intrathymic T-Cell development

“…A recent study supports our findings and defines the role of miR-21 in acting as a critical rheostat facilitating the T-and iNKT-cell response towards low-affinity antigens (Fedeli et al, 2021). Especially for iNKT cells, miR-21 is the most highly upregulated miRNA compared to conventional T cells (Fedeli et al, 2009).…”

“…Surprisingly, absence of miR-21 does not result in altered frequencies of iNKT cells as shown by us and others (Kunze-Schumacher et al, 2018;Fedeli et al, 2021) (Figure 38). In the recent study by Fedeli et al (2021), miR-21 was identified to sustain CD28-dependent costimulation pathways and KO mice showed enhanced resistance towards experimental autoimmune encephalomyelitis. These experiments support our findings of miR-21 rather acting in fine-tuning T-cell responses than controlling a particular step of T-cell development.…”

“…Especially for iNKT cells, miR-21 is the most highly upregulated miRNA compared to conventional T cells (Fedeli et al, 2009). Surprisingly, absence of miR-21 does not result in altered frequencies of iNKT cells as shown by us and others (Kunze-Schumacher et al, 2018;Fedeli et al, 2021) (Figure 38). In the recent study by Fedeli et al (2021), miR-21 was identified to sustain CD28-dependent costimulation pathways and KO mice showed enhanced resistance towards experimental autoimmune encephalomyelitis.…”

“…Unsere Ergebnisse lassen den Schluss zu, dass miR-21 vermutlich intrathymische Prozesse vielmehr feinreguliert, anstatt einen spezifischen Aspekt der T-Zellentwicklung zu beeinflussen. Diese Schlussfolgerung konnte auch durch die jüngsten Arbeiten von Fedeli et al bestätigt werden, die unsere Arbeiten reproduzieren konnten(Fedeli et al, 2021). Eine weitere Studie, die die Rolle von miR-21 in der Leber untersucht, konnte aufzeigen, dass miR-21 ihre Zielgene nur in kanzerösen Zellen effektiv unterdrückt, nicht aber im gesunden Gewebe.…”