UTX Restrains Plasma Cell Formation See article p. 1873

lincRNA-Cox2 Regulates Lung Cytokine Genes See article p. 1886

B Cell m6A Is Required for Optimal Germinal Centers See article p. 1924

Skinks Make Do without γδ T Cells See article p. 1960

Persistence of Virus-Specific Memory Tregs See article p. 1989

In this Top Read, Morrissey et al. (p. 1960) report that the squamate reptile Tiliqua rugosa, a species of skink, completely lacks γδ T cells and the genes that encode the TCRγ- and TCRδ-chains. By comparing several vertebrate spleen transcriptomes and genome databases, the authors show that skinks, and at least two other squamate reptiles, completely lack TRG and TRD genes that are present in all other vertebrates examined to date. Furthermore, whereas the TRA and TRB loci are present in the skink genome, they contain significantly fewer TRAV and TRBV gene segments, which is consistent with reduced complexity in the TCRs on its αβ T cells. Interestingly, the genome of the extant reptile most closely related to skink, the tuatara, showed the presence of an unconventional TRDVH gene within its TRA/D locus that resembles an IgH gene, while no VH gene segment was found in the skink TCR genes. Altogether, the presence of TRG and TRD genes in tuatara and their absence in skink, coupled with the low complexity of skink TRA and TRB genes, suggests that deletion of γδ T cells is an evolutionary adaptation for the skink, and may point toward previously unconsidered compensatory roles of αβ T cells or other immune cells.

In this Top Read, Kania et al. (p. 1873) demonstrated that the demethylase UTX is an epigenetic factor that inhibits plasma cell (PC) differentiation. Although a double-knockout (dKO) of Utx and Jmjd3 resulted in increased numbers of PCs following LPS stimulation, the loss of Utx alone was sufficient to drive PC differentiation. RNA sequencing analysis of dKO marginal zone B cells showed upregulated Myc and MYC target gene expression compared with controls. The authors hypothesized that this change in gene expression likely contributed to the dKO marginal zone proliferative advantage. PCs lacking UTX and JMJD3 also showed an increase in mitochondrial metabolism and a decrease in apoptosis compared with control PCs. Genes for ETS and IRF factors, previously shown to be inhibitors of PC formation, were enriched for methylation, suggesting that UTX may alter the chromatic accessibility of these genes, thereby inhibiting PC differentiation. Together, the findings suggest that demethylation by UTX, in particular, restrains B cell differentiation.

Long intergenic noncoding RNA Cox2 (lincRNA-Cox2) and other noncoding RNAs are actively transcribed regions of the genome that can regulate biological processes such as inflammation. In this Top Read, Robinson et al. (p. 1886), investigated the role of lincRNA-Cox2 during LPS-induced acute lung injury (ALI). The authors found that lincRNA-Cox2 is most highly expressed in alveolar macrophages (AMs) following ALI, as compared with expression in other cell types. lincRNA-Cox2–deficient mice showed dysregulated inflammation, as well as Il6, Ccl3, and Ccl5 cytokine gene expression. The authors showed that lincRNA-Cox2 regulates these cytokine genes in trans following ALI in bone marrow–derived cells. Thus, lincRNA-Cox2 represents a new epigenetic determinant that controls inflammation and maintains homeostasis upon LPS-induced ALI.

In this Top Read, Sariol et al. (p. 1989) showed that virus-specific memory regulatory T cells (Tregs) persisted long-term in the absence of viral Ag. Virus-specific Foxp3+ cells were adoptively transferred into a congenic mouse, subsequently infected with the coronavirus JHMV, or given vehicle. Virus-specific Tregs were detected in the vehicle-treated mice up to 30 d postinfection (dpi), whereas they persisted in JHMV-infected mice through 180 dpi. Viral RNA was undetectable 30 dpi, suggesting that these virus-specific Tregs represent memory Tregs. Compared to naive, virus-specific Tregs, the long-lived Tregs differentially expressed memory and myeloid-associated genes. Following in vivo virus challenge, adoptively transferred memory Tregs had significantly increased proliferation compared with naive cells. Additionally, animals receiving memory Tregs showed fewer IFN-γ+ CD4+ T cells following viral challenge, suggesting that memory Tregs have the ability to ameliorate damage caused by effector cells during viral infection. In summary, virus-specific memory Tregs persist in the absence of cognate Ag and have the ability to respond to and mitigate damage during subsequent viral infection.

In this Top Read, Huang et al. (p. 1924) investigated how the positive selection of germinal center (GC) B cells is modulated posttranscriptionally. Using genetic deletion of methyltransferase like 14 (Mettl14) in GC B cells undergoing somatic hypermutation, the authors showed that Mettl14-mediated adenosine methylation at position N6 of mRNA (m6A) is required for robust responses. Loss of Mettl14 in GC B cells diminished their proliferation and Ab responses compared with controls. Mettl14-mediated m6A modification promoted mRNA decay of negative regulators such as Lax1 and Tipe2. The authors also showed that Mettl14-mediated m6A regulates the expression of genes responsible for regulation of GC B cell positive selection and cell cycle. This activity was Ythdf2 dependent and Myc independent. Collectively, this study demonstrated that Mettl14-mediated m6A modification promotes the maturation of humoral immune responses at the level of the GC B reaction.