TRIMming Up the IFN Response
In this Top Read, Hoffpauir et al. (p. 153) demonstrate that tripartite motif-containing protein 14 (TRIM14) is critical for the induction of type 1 IFN and resolution of Mycobacterium tuberculosis infection in macrophages. Infection upregulated TRIM14, which bound to the kinase TBK1, leading to phosphorylation of STAT3 at S727 and its subsequent translocation into the nucleus. In macrophages lacking TRIM14 (Trim14−/−), STAT3 phosphorylation shifted to the inhibitory S754 position, resulting in decreased STAT3 translocation and a defect in Socs3 induction. Because Socs3 is a negative regulator of IFN, Trim14-deficient macrophages produced more IFN-β than wild type macrophages. In addition to an enhanced IFN response, Trim14-deficient macrophages also produced higher levels of inducible NO, which inhibited replication of M. tuberculosis within macrophages. Together, these data support an important role for TRIM14 in the IFN response to M. tuberculosis infection of macrophages.
Improving MHC Class II Prediction
To date, tools predicting and/or identifying MHC class II (MHC-II) binding peptides are impaired by a high false positive rate. In this Top Read, Osterbye et al. (p. 290) report a novel method to generate large amounts of peptide binding data for specific MHC-II molecules that were used to train artificial neural networks (ANNs), which generate predictive models for binding peptide epitopes. The authors investigated the binding of recombinant HLA-DRB1*01:01 and HLA-DRB1*03:01 to high-density microarrays containing 70,000 random peptides in triplicate. ANN training with the peptide microarray datasets returned prediction models with a very high internal correlation and indicated that the respective HLA-DR molecules contain distinct and recognizable patterns extracted by the algorithm. A direct comparison of the prediction scores between the peptide microarray–driven models and those derived from conventional binding assays revealed comparable performance, suggesting that high-density peptide microarrays can be used to generate relevant peptide–HLA-II binding data. Thus, this approach represents an improved method to generate large amounts of peptide–MHC-II binding data that can improve prediction models.
Inhibition of Necroptosis by Caspase-9 in B Cells
In this Top Read, Zhang et al. (p. 113) show that caspase-9 protects germinal center (GC) B cells and Ab responses by inhibiting necroptosis. IgG1+ GC B cells displayed activated caspase-9 in both naive and 4-hydroxy-3-nitrophenylacetyl–keyhole limpet hemocyanin (NP-KLH)–immunized mice. Naive mice with a B cell–specific deletion of caspase-9 (B/Casp9−/−) displayed normal B cell development. However, B/Casp9−/− mice immunized with NP-KLH showed reductions in the number of NP+ IgG1+ GC B cells and the number of Ag-specific CD138+ plasma cells, suggesting that caspase-9 is important for maintaining Ab responses after immunization. Consistent with previous observations, caspase-9 deficiency in B cells decreased apoptosis and promoted necroptosis, which was also evidenced by increased phosphorylation of Ripk3. Congruently, deletion of both Ripk3 and caspase-9 in B cells decreased cell death in naive animals and restored Ab responses in NP-KLM–immunized mice. Together, these data reveal an important role for caspase-9 in maintaining a balance between apoptosis and necroptosis to protect the homeostasis of GC B cells in Ab responses.
Tracing BCR Self-Reactivity
Although studies of transgenic mice expressing self-reactive BCRs defined mechanisms of immunological tolerance, they are limited due to restricted diversity of the quasi-clonal B cell populations. In this Top Read, Nojima et al. (p. 90) used single B cell cultures, which do not support V(D)J mutation and therefore represent the BCR expressed by each founder B cell, to trace the natural dynamics of autoreactive BCR repertoires in normal mice. In contrast to knock-in models, the absolute frequencies of DNA-reactive B cells in normal mice did not significantly change during B cell development and maturation. Rather, B cells most avid for DNA were lost in the transition from small pre-B to immature and transitional-1 (immature/T1) B cells, revealing the first tolerance checkpoint. DNA reactivity did not significantly change when immature/T1 B cells developed into mature follicular (MF) B cells, suggesting that the second tolerance checkpoint is negligible in removing autoreactive BCRs. Autoreactivity was enriched in the transitional-3 (T3) and CD93+ IgM−/loIgDhi anergic B cells and a CD93− anergic subset in the spleen. Whereas splenic T3 and CD93+ anergic B cells are short-lived, CD93− IgM−/loIgDhi B cells had half-lives comparable to MF B cells. B cell–specific deletion of proapoptotic genes Bak and Bax resulted in increased CD93− IgM−/loIgDhi B cells but not T3 B cell numbers, suggesting that apoptosis differently regulates persistent and short-lived autoreactive B cells. Thus, a persistent, self-reactive compartment may be the origin of systemic autoimmunity and a potential target for therapeutic intervention.
- Copyright © 2020 by The American Association of Immunologists, Inc.
