Overlapping Epitopes in Distinct T Cell Populations
Overlapping CD8 T cell influenza A viral epitopes (NA181-190 and NA181-191) were previously shown to be presented on the surface of APCs by conventional and cross-presentation mechanisms. In this Top Read, Assmus et al. (p. 1731) described a comprehensive analysis of the distinct CD8 T cell populations in vivo that recognize these overlapping epitopes. Based on tetramer staining, the epitopes elicited distinct CD8 T cell responses at both the site of infection and in the spleen. These CD8 T cell populations differed in regard to cytokine responses and cognate TCR avidity. Distinct CDR3 sequences and the NNdistance rank score further indicated that the TCR repertoires induced by these epitopes are distinct. Additionally, tetramer isolation of naïve CD8 T cells showed uniquely specific populations with no cross-reactivity. The unique CD8 T cell responses to overlapping epitopes were driven by conformational changes required to accommodate the additional peptide in NA181–191 into the MHC class I binding groove, thereby presenting a unique epitope surface to TCRs. Together, these data demonstrate that overlapping peptide epitopes have the potential to elicit distinct and functionally unique CD8 T cell responses.
FBXO3 Negatively Regulates Antiviral Responses
A member of the F-box family of proteins, FBXO3, has been reported to play a role in host autoimmune and inflammatory responses by promoting ubiquitylation of phosphorylated autoimmune regulator (AIRE). However, the role it plays during antiviral responses has yet to be elucidated. In this Top Read, Li et al. (p. 1897) demonstrated that overexpression of zebrafish fbxo3 inhibits poly(I:C)- or spring viremia of carp virus (SVCV)-induced IFN activation. Additionally, deletion of fbxo3 increased larval survival rate after SVCV exposure and enhanced key antiviral genes in the spleen and liver, indicating that FBXO3 negatively regulates the antiviral response. Mechanistically, FBXO3 suppressed transcription of IFN regulatory factor (IRF) 3 and IRF7 by promoting K27-linked polyubiquitination, resulting in their proteasomal degradation. Furthermore, the F-box domain of FBOX3 was not required for its interaction with either IRF3 or IRF7. Thus, this study provides novel insights into the function of FBXO3 during antiviral responses and sheds new light on the regulation of IFN-I signaling by F-box proteins.
Native Ag Display on cDC1 Underlies Vaccine Efficacy
In this Top Read, Kato et al (p. 1842) show that Ag targeted to the C-type lectin-like molecule (Clec9A) on type 1 conventional dendritic cells (cDC1) efficiently induces a humoral response. Limiting concentrations of Ag required Clec9A targeting of B epitopes, in addition to T cell epitopes, for effective Ab responses. However, Clec9A-targeted Ag allowed cDC1 to directly activate B cells, independent of follicular T cell help. B cell Ag acquisition from cDC1 was independent of Clec9A targeting. Two-photon and confocal microcopy showed interaction of cDC1s and B cells following Clec9A-targeted Ag administration and migration of early B cells to the T–B cell border of the spleen and lymph node, suggesting that cDC1 present Ag directly to B cells. Ag targeted to Clec9A showed sustained presentation by cDC1 and B cell activation when compared with Ag targeted to another C-type lectin-like molecule. These data demonstrate that Clec9A–Ag targeting could be exploited to enhance humoral responses in vaccine development.
Treg Stability and Migration Are mTOR Dependent
In this Top Read, Vallion et al. (p. 1799) sought to elucidate how the mechanistic target of rapamycin (mTOR) impacts cellular metabolism and biology of Foxp3 regulatory T cells (Tregs). Using a tissue-specific deletion strategy in mice, the authors demonstrated that mTOR is critical for Treg differentiation and migration into nonlymphoid tissues. Additionally, mTOR-deficient Tregs displayed intrinsic metabolic alterations, correlating with increased levels of glutamine-derived metabolites associated with glutaminolysis, the urea cycle pathway, and the tricarboxylic acid cycle. mTOR-deficient Tregs also had reduced stability and Foxp3 expression, which correlated with partial remethylation of the Foxp3 locus. Taken together, this study shows that mTOR is crucial for maintaining Foxp3 expression and regulating Treg differentiation, migration, and integrity.
- Copyright © 2020 by The American Association of Immunologists, Inc.
