Tumor necrosis factor receptor–associated factor 3 (TRAF3) is an adaptor protein that inhibits signaling by CD40 and by the receptor for B cell–activating factor (BAFF) and negatively regulates homeostatic B cell survival. Loss-of-function mutations in TRAF3 are associated with human B cell malignancies, in particular multiple myeloma. The cytokine interleukin-6 (IL-6) supports the differentiation and survival of normal and neoplastic plasma cells. We found that mice with a deficiency in TRAF3 specifically in B cells (B-Traf3−/− mice) had about twice as many plasma cells as did their littermate controls. TRAF3-deficient B cells had enhanced responsiveness to IL-6, and genetic loss of IL-6 in B-Traf3−/− mice restored their plasma cell numbers to normal. TRAF3 inhibited IL-6 receptor (IL-6R)–mediated signaling by facilitating the association of PTPN22 (a nonreceptor protein tyrosine phosphatase) with the kinase Janus-activated kinase 1 (Jak1), which in turn blocked phosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Consistent with these results, the number of plasma cells in the PTPN22-deficient mice was increased compared to that in the wild-type mice. Our findings identify TRAF3 and PTPN22 as inhibitors of IL-6R signaling in B cells and reveal a previously uncharacterized role for TRAF3 in the regulation of plasma cell differentiation.

An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22R620W, is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by two- to fourfold. The NOD mouse is a spontaneous T1D model that shares with humans many genetic pathways contributing to T1D. We hypothesized that the introduction of the murine orthologous Ptpn22R619W mutation to the NOD genome would enhance the spontaneous development of T1D. We microinjected CRISPR-Cas9 and a homology-directed repair template into NOD single-cell zygotes to introduce the Ptpn22R619W mutation to its endogenous locus. The resulting Ptpn22R619W mice showed increased insulin autoantibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22R620W and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice.

Research on procedural justice shows that when people view procedures as fair, they are more satisfied with the process and accepting of the outcomes. The group value model, in particular, argues that people care about procedural justice because it communicates whether those in charge are neutral, trustworthy, and respectful of people's rights. This study tested the group value model using survey data from people attending U.S. Food and Drug Administration advisory committee meetings. The results confirmed a strong role for procedural justice, even when controlling for procedural knowledge, tolerance for potential conflicts of interest among committee members, and respondents' stakes in the outcomes. [T]o seem to be just to the disappointed participant, to retain his allegiance, this must surely be one of the more difficult tests that a decision‐making system can undergo (Thibaut & Walker, 1975, p. 68).

The protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, PTPN22, has wide-ranging effects in immune cells including suppression of T-cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells. Here we show that mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13). The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced. Reduction of CREM expression in wild-type CD4 T lymphocytes prevents the loss of IL-2 production by CD4 T lymphocytes during infection with LCMV cl13. These findings implicate the IFNβ/CREM/IL-2 axis in regulating T-lymphocyte function during chronic viral infection.

Strains of Sindbis virus differ in their virulence for mice of different ages; this variation is related in large part to variations in the amino acid compositions of El and E2, the surface glycoproteins. The comparative pathogenesis of Sindbis virus strains which are virulent or avirulent for newborn mice has not been previously examined. We have studied the diseases caused by a virulent wild-type strain, AR339, and two less virulent laboratory strains, TotollOl and HRSP (HR small plaque). After peripheral inoculation of 1,000 PFU, AR339 causes 100% mortality within 5 days (50% lethal dose [LD50] = 3 PFU) while TotollOl causes 70% mortality (LD50 = 1024 PFU) and HRSP causes 50 to 60% mortality (LD50 = 105's PFU) with most deaths occurring 7 to 11 days after infection. However, after intracerebral inoculation of 1,000 PFU, TotollOl is virulent (100% mortality within 5 days; LDsO = 4 PFU) while HRSP is not (75% mortality; LD5* = 104.2 PFU). After intracerebral inoculation, all three strains initiate new virus formation within 4 h, but HRSP reaches a plateau of 106 PFU/g of brain while TotollOl and AR339 replicate to a level of 108 to 109 PFU/g of brain within 24 h.