NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20.

Natural killer T (NKT) cells are innate lymphocytes that differentiate into NKT1, NKT2, and NKT17 sublineages during development. However, the signaling events that control NKT sublineage specification and differentiation remain poorly understood. Here, we demonstrate that the ubiquitin-modifying enzyme TNFAIP3/A20, an upstream regulator of T cell receptor (TCR) signaling in T cells, is an essential cell-intrinsic regulator of NKT differentiation. A20 is differentially expressed during NKT cell development, regulates NKT cell maturation, and specifically controls the differentiation and survival of NKT1 and NKT2, but not NKT17, sublineages. Remaining A20-deficient NKT1 and NKT2 thymocytes are hyperactivated in vivo and secrete elevated levels of Th1 and Th2 cytokines after TCR ligation in vitro. Defective NKT development was restored by compound deficiency of MALT1, a key downstream component of TCR signaling in T cells. These findings therefore show that negative regulation of TCR signaling during NKT development controls the differentiation and survival of NKT1 and NKT2 cells.

Trends in Métis-related health research (1980-2009): identification of research gaps.

OBJECTIVE: Several literature reviews have highlighted the under-representation of Métis in research regarding Aboriginal Peoples. However, to date, an in-depth examination of trends in Métis research has not been undertaken. This literature review aims to identify trends and gaps in Métis-related health/well-being research over the past three decades (1980-2009). METHODS: Health, medical and social sciences literature databases including Cochrane, CINAHL, Embase, Pubmed, PyschInfo, and Web of Science were searched for Métis-relevant peer-reviewed articles published between 1980 and 2009 via two search strategies: 1) using the terms "Métis," "mixed-blood" or "half-breed," and 2) using a combination of terms: (Aboriginal OR Indigenous OR native OR "First Nation" OR Indian) and (mixed OR European OR Caucasian OR white) and "Canada". Articles pertaining to the health/well-being of Métis in Canada were retained, coded and analyzed by study type/design, gender-specificity, geography, research topic, the extent to which Métis-specific breakdown of findings was provided, and methodological quality relating to validity and reliability of the study. RESULTS: Noteworthy strengths in Métis research were observed, including increasing attention to chronic diseases, diet/nutrition/physical activity, and maternal and child health; a trend towards increased presentation of Métis-specific results among pan-Aboriginal studies, and female-specific and qualitative studies; and an equitable focus on urban and rural areas. Gaps were seen in research related to environment/toxicology, genetics, health delivery/programming/policy, injury, mental health (MH)/addictions, social determinants of health, and violence/crime. In addition, a dearth of male-specific research was identified. Also, most articles were cross-sectional in design. Finally, despite an increase in Métis-related articles over the past three decades, a large proportion of articles remained pan-Aboriginal in nature and did not provide a Métis-specific breakdown of findings. With respect to methodological quality, nearly two thirds of all studies were of strong or moderate quality (cross-sectional studies), good quality (cohort/case-control studies) or acceptable quality (qualitative and mixed methods studies). CONCLUSION: Several gaps exist in Métis-related health/well-being research with respect to study type/design, gender-specificity, research topics, presentation of Métis-specific findings, and methodological quality. In addition to specific gaps, the overall limited number of research articles/studies needs to be recognized. These deficiencies could be alleviated by increasing targeted funding and support for Métis-related research, and removing barriers to Métis-specific research. Addressing gaps in Métis health research will enable identification of appropriate targets for intervention and, subsequently, design, development and evaluation of interventions to address Métis health disparities and their determinants.