CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.

Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.

Lessons Learned from Clinicians in a Federally Qualified Health Center: Steps Toward Eliminating Burnout.

Background: Burnout continues to impact health care workers and its effect takes a toll on their lives and wellbeing, especially in primary care. Relatively few studies have focused specifically on the perspective of clinicians in Federally Qualified Health Centers (FQHCs), which offer crucial, preventative health care services to vulnerable and underserved patient populations. Objective: To examine the perspectives of clinicians working at an FQHC in the Northeast United States after the implementation of a year-long wellness initiative. Design: A qualitative analysis of clinician's discussion during focus groups conducted after the wellness initiative. Subjects and Setting/Location: A total of 28 clinicians (primary care physicians and nurse practitioners) in an FQHC in the Northeast United States. Interventions: A one-year wellness initiative with programs and activities designed to bolster wellness. Outcome Measures: Analyzed NVIVO-coded transcripts of focus group discussion to generate codes and used modified grounded theory to extrapolate meaningful themes. Results: Five key themes emerged from the qualitative analysis: (1) clinicians often felt burdened by their workload and personally responsible when they were not able to provide optimal care to patients; (2) burnout was exacerbated by systemic problems at the FQHC; (3) medical assistants, medical scribes, schedulers, and other support staff played a crucial role in the wellness of the entire team; (4) perceived differences in priorities between administration and health care workers may have contributed to burnout; and (5) a communicative and stable team helped clinicians effectively care for their patients. Conclusions: Clinician burnout is a complex problem at FQHCs with many root causes. Addressing burnout and improving clinician wellness at FQHCs will require a multifaceted approach encompassing systemic, team, and individual components. The perspectives from the clinicians at our FQHC may inform wellness strategies for other safety net, clinical institutions in the primary care setting.