Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells.

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.

NF-κB Protects NKT Cells from Tumor Necrosis Factor Receptor 1-induced Death.

Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-xL-coding Bcl2l1 transgene into NF-κB signalling-deficient IκBΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas. Surprisingly, the single and combined deficiency in PKC-θ or CARMA-1-the two signal transducers at the NKT TCR proximal signalling node-only partially recapitulated the NKT cell deficiency observed in IκBΔN tg mouse. Accordingly, introgression of the Bcl2l1 transgene into PKC-θ null mouse failed to rescue NKT cell development. Instead, TNFR1-deficiency, but not the Fas-deficiency, rescued NKT cell development in IκBΔN tg mice. Consistent with this finding, treatment of thymocytes with an antagonist of the inhibitor of κB kinase -which blocks downstream NF-κB activation- sensitized NKT cells to TNF-α-induced cell death in vitro. Hence, we conclude that signal integration by NF-κB protects developing NKT cells from death signals emanating from TNFR1, but not from the NKT TCR or Fas.

Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective.

Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective.

A Distinct Lung-Interstitium-Resident Memory CD8(+) T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection.

The nature and anatomic location of the protective memory CD8(+) T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8(+) T cells and their role in lower airway infections. Memory CD8(+) T cells elicited by local intranasal, but not systemic, vaccination with an engineered non-replicative CD8(+) T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3(LO) resident memory CD8(+) T (Trm) cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial Trm cells act before inflammation can recruit circulating memory CD8(+) T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial Trm cells may confer better protection against respiratory pathogens.

Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.

The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.

Discovering protective CD8 T cell epitopes--no single immunologic property predicts it!

Once a burgeoning field of study, over the past decade or so, T cell epitope discovery has lost some luster. The contributory factors perchance are the general notion that any newly discovered epitope will reveal very little about an immune response and that knowledge of epitopes are less critical for vaccine design. Despite these notions, the breadth and depth of T cell epitopes derived from clinically important microbial agents of human diseases largely remain ill defined. We review here a flurry of recent reports that have rebirthed the field. These reports reveal that epitope discovery is an essential step toward rational vaccine design and critical for monitoring vaccination efficacy. The new findings also indicate that neither immunogenicity nor immunodominance predict protective immunity. Hence, an immunogenic epitope is but a peptide unless proven protective against disease.

Polytetrafluoroethylene patch repair of a saccular abdominal aortic aneurysm in a 5-year-old boy.

A 5-year-old boy presented with acute abdominal pain and was subsequently found to have an abdominal aortic aneurysm. The aetiology remains obscure. Repair was accomplished with a PTFE patch and he remains well on follow up.

An analysis of a health professions appeal board--should a mediational style of hearing matters be adopted?

The Ontario Health Professions Board is a statutory Board that carries out a supervisory function and review function of certain matters arising from twenty-three health professions in the province. This paper examines the board, how it functions, and the nature and type of disputes, which come before it. Having regard to key concepts in the areas of conflict analysis and process design, the paper critically discusses whether the Board ought to adopt a mediational style of hearing matters. The conclusions are that there are very real dangers that the current practices of the Board may contribute to conflict rather than resolve it, that there is no legal impediment to the Board adopting a mediational style of hearing matters, and that such an approach would contribute to the Board effectively carrying out its statutory functions.