TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1 mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.

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Purpose: The Royal College of Physicians and Surgeons of Canada (RCPSC) has mandated the transition of postgraduate medical training in Canada to a competency-based medical education (CBME) model divided into 4 stages of training. As part of the Queen’s University Fundamental Innovations in Residency Education proposal, Queen’s University in Canada is the first institution to transition all of its residency programs simultaneously to this model, including Diagnostic Radiology. The objective of this report is to describe the Queen’s Diagnostic Radiology Residency Program’s implementation of a CBME curriculum. Methods: At Queen’s University, the novel curriculum was developed using the RCPSC’s competency continuum and the CanMEDS framework to create radiology-specific entrustable professional activities (EPAs) and milestones. In addition, new committees and assessment strategies were established. As of July 2015, 3 cohorts of residents (n = 9) have been enrolled in this new curriculum. Results: EPAs, milestones, and methods of evaluation for the Transition to Discipline and Foundations of Discipline stages, as well as the opportunities and challenges associated with the implementation of a competency-based curriculum in a Diagnostic Radiology Residency Program, are described. Challenges include the increased frequency of resident assessments, establishing stage-specific learner expectations, and the creation of volumetric guidelines for case reporting and procedures. Conclusions: Development of a novel CBME curriculum requires significant resources and dedicated administrative time within an academic Radiology department. This article highlights challenges and provides guidance for this process.

The persistence of memory lymphocytes is a critical feature of adaptive immunity. The TNF family ligand 4-1BBL supports the antigen-independent survival of CD8 + memory T cells. Here, we show that mice lacking 4-1BB only on αβ T cells show a similar defect in CD8 + T-cell recall responses, as previously shown in 4-1BBL-deficient mice. We show that 4-1BB is selectively expressed on BM CD8 + but not CD4 + memory T cells of unimmunized mice. Its ligand, 4-1BBL, is found on VCAM-1 + stromal cells, CD11c + cells, and a Gr1 lo myeloid population in unimmunized mice. Adoptive transfer of in vitro generated memory T cells into mice lacking 4-1BBL only on radioresistant cells recapitulates the defect in CD8 + T-cell survival seen in the complete knockout mice, with smaller effects of 4-1BBL on hematopoietic cells. In BM, adoptively transferred DsRed CD8 + memory T cells are most often found in proximity to VCAM-1 + cells or Gr1 + cells, followed by B220 + cells and to a much lesser extent near CD11c + cells. Thus, a VCAM-1 + CD45 − stromal cell is a plausible candidate for the radioresistant cell that provides 4-1BBL to CD8 + memory T cells in the BM.Keywords: 4-1BB r Bone marrow chimeras r CD8 + T-cell memory r CD137 r Stromal cells Supporting Information available online IntroductionImmunological memory is a key feature of our adaptive immune system. The persistence of memory lymphocytes affords the host long-term protection against reinfection. It is thought that lymphocytes must compete for space in defined cellular niches that are specific to a particular subset of lymphocytes [1,2]. The cell types and key molecular components that make up the supportCorrespondence: Dr. Tania H. Watts e-mail: tania.watts@utoronto.ca ive niches for memory T cells are beginning to be defined [3][4][5][6]. These niches are expected to contain the chemokines that attract the lymphocytes to the site [3,7], the adhesion molecules that provide retention signals at the site [5,7], as well as the common γ-chain (γ c ) cytokines that provide homeostatic proliferative signals to the lymphocytes [8].For CD8 + T cells, there is strong evidence that both IL-15 and IL-7 are required for their maintenance [8][9][10][11][12][13][14][15][16][17]. CD8 + CD44 Hi memory phenotype T cells home to and are enriched in the BM [7,18]. Moreover, the BM contains virus-specific memory T cells that can protect against reinfection [19], and CD8 + memory T cells in the BM show evidence of homeostatic proliferation C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2862 Gloria H. Y. Lin et al. Eur. J. Immunol. 2012. 42: 2861-2874 [20,21], independently of secondary lymphoid organs [22]. Thus, it has been proposed that the BM is a major site for homeostatic proliferation of CD8 + memory T cells [23]. However, there is limited evidence as to the nature of the BM niches that support the proliferation and survival of these cells. In addition to a requirement for chemokines, γ c cytokines, and adhesion molecules, emerging data also suggest that ligan...

Lymphocytic choriomeningitis virus clone 13 (LCMV13) infection of mice is a widely used model for investigating the mechanisms driving persistent viral infection in humans.LCMV13 disrupts splenic architecture early during infection, but this returns to normal within a few weeks. However, the long-term effects of LCMV13 infection on splenic structure have not been reported. Here, we report that persistent infection with LCMV13 results in sustained splenic atrophy that persists for at least 500 days following infection, whereas infection with the acutely infecting LCMV Armstrong is associated with a return to preinfection spleen weights. Splenic atrophy is associated with loss of T, B, and non-B non-T cells, with B cells most significantly affected. These effects were partly ameliorated by anti-NK1.1 or anti-CD8 antibody treatment. Antigen presentation was detectable at the time of contraction of the spleen, but no longer detected at late time points, suggesting that continued antigen presentation is not required to maintain splenic atrophy. Immunity to Salmonella infection and influenza vaccination were decreased after the virus was no longer detected. Thus splenic atrophy following LCMV13 infection is irreversible and may contribute to impaired immunity following clearance of LCMV13. Keywords: CD8 + T cells Influenza LCMV NK cells Splenic atrophy SalmonellaAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionLymphocytic choriomeningitis virus (LCMV) is a noncytopathic rodent pathogen. Infection with LCMV Armstrong leads to a robust CD8 + T cell response that results in rapid clearance of this acutely infecting strain of the virus. LCMV clone 13 (LCMV13) is a variant of LCMV Armstrong, isolated by serial passage in mice [1], that differs by only three amino acids [2], resulting in a persistent viral infection that is ultimately cleared from most organs Correspondence: Dr. Tania H. Watts e-mail: tania.watts@utoronto.ca by 60-90 days postinfection (dpi). LCMV13 infection of mice is a widely used model to study the mechanisms driving persistent viral infection and has provided valuable insights into how such mechanisms could be manipulated to treat chronic human viral disease and other chronic conditions, such as cancer [3][4][5][6]. Despite the noncytopathic nature of the virus, chronic infection with LCMV is associated with specific and generalized immunosuppression [7] due at least in part to the induction of immunoregulatory mechanisms as a consequence of persistent immune stimulation. This immune regulation leads to functional exhaustion of the immune system [4][5][6]. Included in these outcomes is the loss of function as well as early depletion of anti-viral T cells, culminating in poor viral control.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2017. 47: 94-106 Immunity to infection 95Previous studies have shown that infection with various strains of LCMV, including WE and clone 13, leads to disr...