MicroRNAs in Tfh Cells: Micromanaging Inflammaging
2014; Cell Press; Volume: 41; Issue: 4 Linguagem: Inglês
10.1016/j.immuni.2014.10.003
ISSN1097-4180
Autores Tópico(s)Circular RNAs in diseases
ResumoMicroRNA (miR)-146a-deficient mice develop low-grade, chronic, and systemic inflammation, similar to inflammaging. Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar demonstrate that the lack of miR-155 prevents the accumulation of Tfh cells and inflammaging in miR-146a-deficient mice. They identify Fosl2 as a functionally important target of miR-155 in Tfh cells. MicroRNA (miR)-146a-deficient mice develop low-grade, chronic, and systemic inflammation, similar to inflammaging. Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar demonstrate that the lack of miR-155 prevents the accumulation of Tfh cells and inflammaging in miR-146a-deficient mice. They identify Fosl2 as a functionally important target of miR-155 in Tfh cells. An efficient immune system mounts potent immune responses to defend against external and internal threats and then resolve the response once the threat is eliminated. Although human beings are living longer, we realize advanced age is also accompanied by defects in both initiation and resolution of immune responses. In the elderly, declining immune responsiveness (immunosenescence) causes increased susceptibility to infections and impaired efficacy of vaccination; and paradoxically, unresolved low-grade inflammation (inflammaging) is associated with cardiovascular disease, cancer, and other end-organ diseases. Compared to younger adults, the immune system in older adults is characterized with reduced naive T cells, increased memory differentiation, and elevated amounts of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Such changes likely result from chronic antigen exposure in the elderly. Consistent with this observation, HIV-infected individuals, even under antiretroviral therapy, demonstrate accelerated “aging” of the immune system (Deeks, 2011Deeks S.G. Annu. Rev. Med. 2011; 62: 141-155Crossref PubMed Scopus (918) Google Scholar). In this issue of Immunity, Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar identify two microRNAs (miRNAs), miR-155 and miR-146a, that regulate follicular helper T (Tfh) cell differentiation and the accumulation during chronic and low-grade inflammation. Not only does the new study extend our knowledge on the sophisticated regulatory circuit in Tfh cells, but it also paves the way to understand the previously unappreciated role for Tfh cells in inflammaging. Tfh cells are a subset of CD4+ helper T cells specialized in regulating antibody responses. In germinal centers (GCs), Tfh cells express costimulatory receptors on the surface and secrete helper cytokines to support GC B cells to undergo multiple rounds of mutation-selection in B cell receptors. In the current model, upon optimal cognate interactions with Tfh cells, high-affinity GC B cells differentiate into memory B cells and plasma cells (Ma et al., 2012Ma C.S. Deenick E.K. Batten M. Tangye S.G. J. Exp. Med. 2012; 209: 1241-1253Crossref PubMed Scopus (400) Google Scholar). The differentiation and function of Tfh cells are critically regulated by transcription factors, with Bcl6, STAT3, Ascl2, IRF4, BATF, and c-MAF generating a major driving force and Blimp-1, STAT5, Foxo1, and Foxp1 acting to antagonize (Ma et al., 2012Ma C.S. Deenick E.K. Batten M. Tangye S.G. J. Exp. Med. 2012; 209: 1241-1253Crossref PubMed Scopus (400) Google Scholar, Yu et al., 2014Yu D. Chen Y. Leong Y.A. Nat. Immunol. 2014; 15: 597-599Crossref PubMed Scopus (2) Google Scholar) (Figure 1). In addition to such transcriptional regulation, there is emerging evidence that miRNA-mediated posttranscriptional regulation also joins the regulatory network to determine the Tfh cell fate. MiRNAs are endogenously produced small RNAs (∼21 nucleotides) that target specific mRNAs through partially complementary base-pairing to destabilize target mRNAs and inhibit their translation (Baumjohann and Ansel, 2013Baumjohann D. Ansel K.M. Nat. Rev. Immunol. 2013; 13: 666-678Crossref PubMed Scopus (284) Google Scholar). Blocking miRNA biogenesis impairs CD4+ T cell proliferation and survival. Each T helper (Th) cell subset displays a distinct miRNA expression profile, and many miRNAs have been identified with specific functions in individual Th cell subsets (summary in Baumjohann and Ansel, 2013Baumjohann D. Ansel K.M. Nat. Rev. Immunol. 2013; 13: 666-678Crossref PubMed Scopus (284) Google Scholar). Notably, miRNA expression is especially important for Tfh cell differentiation. Without global miRNA expression, Tfh cell differentiation is severely impaired, whereas the differentiation of other Th subsets, particularly Th1, is enhanced. This defect of Tfh cell differentiation can be partially explained by the lack of a miRNA cluster, miR-17-92. MiR-17-92 is induced early in CD4+ T cell activation, peaks at the early stage of differentiation, and then decreases to an amount lower than that in naive CD4+ T cells. The upregulation of miR-17-92 during initial activation is considered to suppress the expression of two phosphatases PTEN and PHLPP2 to remove the inhibition of ICOS-PI3K-Akt signaling pathway to promote Tfh cell differentiation. It might also suppress the expression of the transcription factor Rora to prevent alternative differentiation into Th17 cells (Baumjohann and Ansel, 2013Baumjohann D. Ansel K.M. Nat. Rev. Immunol. 2013; 13: 666-678Crossref PubMed Scopus (284) Google Scholar) (Figure 1). In this new study, Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar revealed additional miRNAs playing roles in the regulation of Tfh cells. Previously, miR-146a-deficient mice were shown to develop systemic inflammatory and autoimmune pathology. Although both myeloid hyperproliferation and dysfunctional regulatory T (Treg) cells contribute to this phenotype, miR-146a deficiency in conventional T cells is sufficient to drive chronic inflammation in an autonomous manner (Yang et al., 2012Yang L. Boldin M.P. Yu Y. Liu C.S. Ea C.K. Ramakrishnan P. Taganov K.D. Zhao J.L. Baltimore D. J. Exp. Med. 2012; 209: 1655-1670Crossref PubMed Scopus (236) Google Scholar). T cell receptor (TCR) stimulation induces the activation of NF-κB and subsequently upregulates the expression of miR-146a. MiR-146a serves as a negative-feedback regulator. It represses the NF-κB signaling transducer TRAF6 and IRAK1 to curb NF-κB activity (Yang et al., 2012Yang L. Boldin M.P. Yu Y. Liu C.S. Ea C.K. Ramakrishnan P. Taganov K.D. Zhao J.L. Baltimore D. J. Exp. Med. 2012; 209: 1655-1670Crossref PubMed Scopus (236) Google Scholar) (Figure 1). Over time, CD4+ T cells from mice deficient of miR-146a became biased to Tfh cell differentiation, with mild changes in Th1 and Th17 cell differentiation (Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar). It is not unexpected that enhanced NF-κB signaling in miR-146a-deficient mice promotes Tfh cell accumulation. Tfh cell differentiation and maintenance requires lasting TCR signaling and chronic antigenic stimulation as seen in viral persistence progressively redirects CD4+ T cell differentiation away from the Th1 cell response induced during an acute infection toward Tfh cells (Ma et al., 2012Ma C.S. Deenick E.K. Batten M. Tangye S.G. J. Exp. Med. 2012; 209: 1241-1253Crossref PubMed Scopus (400) Google Scholar). Accumulation of Tfh cells in miR-146a-deficient mice in advancing age was associated with spontaneous GC formation and autoantibody production (Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar). Active differentiation of Tfh cells driving autoantibody production is a feature of autoimmune patients such as those with systemic lupus erythematosus (SLE) (He et al., 2013He J. Tsai L.M. Leong Y.A. Hu X. Ma C.S. Chevalier N. Sun X. Vandenberg K. Rockman S. Ding Y. et al.Immunity. 2013; 39: 770-781Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). Intriguingly, SLE patients were reported with miR-146a underexpression and the association with a high-risk allele carrying a functional variant in miR-146a promoter impairing its induction (Shen et al., 2012Shen N. Liang D. Tang Y. de Vries N. Tak P.P. Nat Rev Rheumatol. 2012; 8: 701-709Crossref PubMed Scopus (125) Google Scholar). Future studies are required to determine the relationship between miRNA-146a underexpression and Tfh cell functionality in human diseases. As “a tale of two miRNAs,” the authors identified miR-155 as a negative regulator in miR-146a-deficiency-induced inflammaging. Mice deficient with both miR-155 and miR-146a showed no accumulation of Tfh cells and GCs. Importantly, inflammatory and autoimmune pathologies in miR-146a-deficient mice are completely prevented by the lack of miR-155. Therefore, loss of miR-155 is essentially epistatic to a deficiency in miR-146a for the inflammaging phenotype. This notion is also supported by the clustering analysis of gene expression in CD4+ T cells from wild-type (WT), single, or double gene-deficient mice, which indicated that the gene-expression profile from double gene-deficient CD4+ T cells was closest clustered with that from Mir155−/− cells (Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar). A similar observation was reported in Th1 cell response for antitumor immunity. Mir146−/− mice possessed enhanced Th1 cell response and better inhibition of tumor growth, whereas both Mir155−/− and Mir155−/−Mir146−/− mice demonstrated dampened IFN-γ production in CD4+ and CD8+ T cells with worse tumor growth than WT mice (Huffaker et al., 2012Huffaker T.B. Hu R. Runtsch M.C. Bake E. Chen X. Zhao J. Round J.L. Baltimore D. O’Connell R.M. Cell Reports. 2012; 2: 1697-1709Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). TCR engagement induces mir-155 expression. MiR-155 is required for Th1 cell differentiation and Mir155−/− CD4+ T cells preferentially differentiate into the Th2 cell subset. Several targets for miR-155 have been studied: c-MAF, SOCS1, SHIP1, and IFN-γRα. Nevertheless, there is a certain discrepancy of target validation. One explanation is that the significance of each regulation might be cell-type and immune-response dependent (Lind and Ohashi, 2014Lind E.F. Ohashi P.S. Eur. J. Immunol. 2014; 44: 11-15Crossref PubMed Scopus (56) Google Scholar). By generating miR-155 conditional gene deletion mice in T cells (Cd4-cre), the authors convincingly revealed the intrinsic requirement of miR-155 in CD4+ T cells for Tfh cell differentiation, in models of protein antigen immunization, infection, and miR-146a-deficiency-induced inflammaging. The defect of Tfh cell function due to miR-155 deficiency in CD4+ T cells led to the reduction of GC formation and antigen-specific antibody production. Hu et al. use a systemic biology approach to search for miR-155 targets specifically in Tfh cells and identified two new targets: Fosl2 and Peli1. Indeed, knockdown of Fosl2 in Mir155−/− CD4+ T cells markedly rescued the generation of Tfh cells (Hu et al., 2014Hu R. Kagele D.A. Huffaker T.B. Runtsch M.C. Alexander M. Liu J. Bake E. Su W. Williams M.A. Rao D.S. et al.Immunity. 2014; 41 (this issue): 605-619Abstract Full Text Full Text PDF Scopus (123) Google Scholar). It is conceived that higher amounts of Fosl2 in Mir155−/− CD4+ T cells increase the competition with BATF to recruit IRF4. Therefore, Tfh cell differentiation is inhibited due to weaker BATF and IRF4 functions (Figure 1). This study uncovers the new role of miR-146a and miR-155. They have now joined with other transcription factors and miRNAs in a regulatory circuit for Tfh cell differentiation and function. Data shown here highlight the importance of sustained TCR signaling and costimulatory signaling to induce the activation of the PI3K-Akt pathway for Tfh cell differentiation (Figure 1). Future investigation is required to dissect synergetic and antagonistic relationships among these regulatory elements and also to understand the stepwise specificity of the regulation at different stages including initiation, differentiation, and maintenance of Tfh cells. The study sheds light on the possible role of Tfh cells, GC response, and autoantibodies in the process of inflammaging. It will be interesting to examine the development of inflammatory pathology in miR146a-deficient mice or other models by preventing Tfh cell function via miR-155 deficiency or other means. If the pathogenic role of Tfh cells and GC responses is confirmed, approaches can be taken to target this pathway to ameliorate inflammation for a healthier aging. miR-155 Promotes T Follicular Helper Cell Accumulation during Chronic, Low-Grade InflammationHu et al.ImmunityOctober 16, 2014In BriefMechanisms that control chronic, low-grade inflammation are poorly understood despite the propensity of this condition to progress to serious diseases. O’Connell and colleagues demonstrate that miR-155 and miR-146a regulate T follicular helper cell development, spontaneous germinal center formation, and autoantibody production in a mouse model of chronic inflammation. Full-Text PDF Open Archive
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