Minor Changes, Major Consequences in RA Diagnostics See article p. 3211

Modifying Marmoset EAE through Diet See article p. 3229

Memory T Cells Are Resistant to Change See article p. 3282

NK Cells Need Notch See article p. 3307

TRAF2: A Key Manager for B Cell Business See article p. 3421

Studies in murine models of experimental autoimmune encephalomyelitis (EAE) have indicated that gut microbiota may impact disease progression. However, it is unclear if these observations may be translated into humans. Kap et al. (p. 3229) showed a reduction in EAE incidence induced with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) and an increase in the time from disease onset in marmosets fed a diet modified with a yogurt-based supplement (YBS), which doubled vitamin B and fiber intake when compared with a water based supplement (WBS). These changes also coincided with a reduction in CalHV3 expression in the colony, an Epstein-Barr–related γ1-herpesvirus associated with EAE etiology. In a study of marmoset twins, EAE incidence was restored in YBS-fed siblings reverted to a WBS diet 8 wk prior to induction with myelin. YBS-fed animals also displayed reduced proinflammatory T cell responses to rhMOG, and apoptosis, but enhanced myelination in the brain. Prior to EAE induction, gut microbiota were mainly represented by Bifidobacteria. Remarkably, twins fed a different diet for several weeks prior to EAE induction displayed no differences in microbiota composition. Differences in gut microbiota were first detectable 3 wk after immunization, coinciding with Ab responses against rhMOG, and were more evident seven wks after rhMOG immunization, with a higher abundance of Bifidobacteria in YBS-fed animals. In conclusion, this study demonstrates that dietary intervention may exert positive changes on EAE parameters in multiple aspects of the gut-immune–CNS axis.

Whereas numerous studies have demonstrated that naive CD8+ T cells show phenotypic and functional plasticity, the nimbleness of memory CD8+ T cells is not well understood. In this issue, Harland et al. (p. 3282) investigated the potential of influenza A virus (IAV)-specific memory CD8+ T cells to alter their phenotype and function in response to activation in the presence of IL-4 and anti–IFN-γ Ab (type 2 conditions). When activated under these conditions, only a small fraction of IAV-specific memory CD8+ T cells (6%) lost surface CD8 expression when compared with naive CD8+ T cells, which completely lost expression of this surface marker. In memory CD8+ T cells, loss of CD8 expression was associated with increased DNA methylation at the Cd8a locus and induction of Il4 and GATA-3 expression. Central memory CD8+ T cells (TCM) were more responsive to type 2 conditions than CD8+ effector T cells. Although reactivation of IAV-specific memory CD8+ T cells under type 2 conditions increased levels of its mRNA, IL-4 protein was not detected. Rather, these cells showed enhanced IFN-γ production. Thus, a small population of memory CD8+ T cells, especially TCM, exhibit phenotypic plasticity, but most Ag-specific memory CD8+ T cells retain the phenotype acquired in response to primary infection.

B cell responses to T cell–dependent (TD) Ags require CD40 signaling to activate NF-κB, which promotes expression of activation-induced cytidine deaminase (AID) and drives class switch recombination (CSR). In this issue, Woolaver et al. (p. 3421) examine the roles of TNFR-associated factor 2 and 3 (TRAF2 and TRAF3) in CD40-driven signaling in B cells. They engineered mice with B cell–specific deletions of TRAF2 or TRAF3 and observed that TD humoral responses were dramatically impaired in B-TRAF2-KO but not B-TRAF3-KO mice. Ex vivo studies confirmed that CD40-driven CSR is strikingly reduced in B-TRAF2-KO B cells compared with B-TRAF3-KO B cells or littermate controls. TRAF2 was critical for activation of the NF-κB1 complex in response to CD40 engagement, and restoration of NF-κB1 activity could rescue this defect in B-TRAF2-KO B cells. These results define a unique role for TRAF2 in TD humoral immunity and clarify previous observations that could not clearly delineate distinguish contributions of TRAF2 and TRAF3.

Anti–citrullinated protein/peptide Abs (ACPA) are present in the majority of patients with rheumatoid arthritis (RA) and recognize epitopes generated by the posttranslational modification known as citrullination. Cornillet et al. (p. 3211) describe the development of an ELISA in which ACPA are screened against a panel of citrullinated fibrin peptides that had minor changes in peptide length or biotin location. They screened the reactivity of 120 sera samples against this panel of 30 peptides and observed that some patient samples showed positive binding to certain epitopes but not others, indicating that peptide characteristics can dramatically impact parameters used to determine serological status of RA patients. The distance between the biotin molecule and Ab epitope was a key parameter in dictating Ab recognition, revealing a role for peptide length in Ab binding. Together, these findings highlight the importance of peptide design for Ab recognition, which can profoundly impact the accuracy of ACPA tests in RA patients or in similar ELISA-based diagnostics.

Notch signaling is essential to T cell lineage commitment; however, its role in NK cell development remains unclear. To study this problem, Chaves et al. (p. 3307) used Rbp-Jkfl/flVav-Cretg/+ mice, which have a specific deletion of Rbp-Jk, a canonical Notch signaling mediator, in hematopoietic cells. The authors observed fewer NK cell progenitors in the bone marrows and a reduction in mature NK cells in the spleens of mutant mice. Gene expression analysis revealed dysregulation of multiple genes essential to NK cell development in the absence of canonical Notch signaling, and these defects are cell intrinsic. Despite the reduction in their numbers, the remaining mature cytotoxic NK cells in the mutant animals displayed a hyperactivated phenotype. Taken together, these data indicate that canonical Notch signaling is critical for NK cell maturation and modulates mature NK cell function.