Regulation of immune responses and tolerance: the microRNA perspective

Abstract

Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNA (miRNA) genes, an abundant class of non-coding RNA genes that produce characteristic approximately 22 nucleotides small RNAs, play important roles in immune cells. In this article, we discuss emerging knowledge regarding the functions of miRNA genes in the immune system. We delve into the roles of miRNAs in regulating signaling strength and threshold, homeostasis, and the dynamics of the immune response and tolerance during normal and pathogenic immunological conditions. We also present observations based on analyzes of miR-181 family genes that indicate the potential functions of primary and/or precursor miRNAs in target recognition and explore the impact of these findings on target identification. Finally, we illustrate that despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses. Tuning miRNA functions in immune cells, through gain- and loss-of-function approaches in mice, may reveal novel approach to restore immune equilibrium from pathogenic conditions, such as autoimmune disease and leukemia, without significant toxicity.

Fig. 1

Representative scenarios of phenotype penetrance caused by genetic manipulation of (A) switching (on/off) molecules and (B) tuning molecules on the immune system at the molecular, cellular, and system layers.

Fig. 2. Control of evolutionarily selected target networks by miRNA species at the post-transcriptional levels

The regulatory information for target recognition and degree of repression is encoded in the nucleotide sequence of miRNA genes. Understanding how such regulatory information is translated into activity is essential in decoding the target networks controlled by miRNA gene products. It is important to note that the major RNA species made from a miRNA gene – primary, precursor, and mature miRNA – all contain the same mature miRNA sequence and, in principle, can bind mRNA targets. The optimal method for computational and experimental target identification will differ depending on which miRNA species are the target-recognizing species.

Fig. 3. Basic models of miRNA target recognition and the corresponding functional consequences

(A) Linear, (B) divergent, (C) network, and (D) convergent model of target control by miRNA species.

Fig. 4. Models of miRNA-controlled signaling networks and the potential impact of miRNA regulation on the strength and threshold of signaling

(A) miRNAs as negative feedback to dampen the expression of multiple positive signaling molecules. (B) miRNAs as a positive feedback to dampen a single negative signaling molecule. (C) miRNAs as a negative tuner of immune signaling by controlling the expression of multiple negative signaling molecules. (D) Effects of miRNA control on the strength and threshold of immune signaling. A1, A2, and An represent positive signaling molecules in the pathway (i.e. the positive kinases). B1, B2, and Bn represent negative signaling molecules in the pathway (i.e. the phosphatases that inactive positive kinases).

Fig. 5. miRNA control of immune signaling

(A) Multi-dimensional control of immune signaling by miRNAs. The strength and spatiotemporal of immune signaling may be controlled by differential miRNA expression. (B) miRNAs as modular signaling regulators. An miRNA can control the same or different signaling pathways in different cell populations. Schematic of thymic T-cell development and signaling pathways controlled by miR-181a these cell populations. Cell types and corresponding signal pathways controlled by miR-181a are matched by color codes.

Fig. 6. miRNA control of normal lineage differentiation and leukeomogenesis

(A) Schematic depicting the parameters that are important for hematopoietic/lymphoid lineage differentiation. (B) Tumor transformation by driver mutations in oncogenes and tumor suppressors and effects on the loss of homeostasis maintenance mechanisms. (C) Targeted inhibition of driver oncogenes and miRNAs has distinct effects on normal and leukemogenic lineage development.

Fig. 7. Pri/pre-miRNAs are potential target-recognizing RNA species of a miRNA gene

(A) Schematics of mir-181a-1 and mir-181c. (B) Mature miR-181a and miR-181c. (C) Pri-/pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in promoting early T cell development. Effects of domain-swapping mutations on the activities of mir-181a-1 and mir-181c in promoting early T-cell development. See Liu et al. (33) for complete data and in depth analyses.