Abstract

The activity of a Natural Killer (NK) cells is regulated by the collective balance of activating and inhibitory signals from surface receptors. The work described here focuses on the biology of human NK receptors, NKG2D & NKR-P1A.

NKG2D recognizes stress-inducible ligands present on virally infected cells, cancer cells, & cells that have experienced genotoxic damage. While NKG2D does not contain any recognizable signaling motifs, it was previously known to pair with a transmembrane adapter signaling protein, DAP10, to initiate signal transduction events. More recently, studies have revealed that alternative mRNA splicing of the mouse NKG2D gene generates receptors that associate with either the DAP10 or DAP12 transmembrane adapter signaling proteins. Here we report that NKG2D function is normal in human patients lacking functional DAP12, indicating that DAP10 is sufficient for human NKG2D signal transduction. Further, we show that human NKG2D is incapable of associating with DAP12 and provide evidence that structural differences in the transmembrane of mouse and human NKG2D account for the species-specific difference for this immune receptor.

Another C-type lectin whose function has remained largely enigmatic is human NKR-P1A (CD161), present on NK cells and subsets of T cells. In these studies, we demonstrate that lectin-like transcript-1 (LLT1) is a physiological ligand for NKR-P1A. LLT1-containing liposomes bind to NKR-P1A+ cells and binding is inhibited by anti-NKR-P1A mAb. Additionally, LLT1 activates NFAT-GFP reporter cells expressing a CD3ζ-NKR-P1A chimeric receptor; reciprocally, reporter cells with a CD3ζ -LLT1 chimeric receptor are stimulated by NKR-P1A. Moreover, LLT1 on target cells can inhibit NK cytotoxicity and cytokine production via interactions with NKR-P1A.

We further demonstrate that Lectin-like Transcript 1 is expressed on activated lymphocytes. We show that activated primary B cells and many B cell lines express LLT1, activated plasmacytoid dendritic cells and activated monocyte-derived dendritic cells express LLT1, and interestingly, activated T cells seem to express LLT1 as well. Lastly we explore the role of NKR-P1A on T cells and find that while engaging NKR-P1A with antibodies on CD8+ T cells can inhibit TNFα production, NKR-P1A does not seem to play any obvious role in CD4+ T cell cytokine production.

Introduction: In 2012 the Accreditation Council for Graduate Medical Education implemented trainee milestones as tools for clinical competency committees to use for evaluation, feedback, remediation, and promotion purposes. Prior to this innovation, there has not been an adequate method to capture, organize, and graphically illustrate the evaluations by attendings in a simple, fast and organized fashion.

Methods: We created a novel, web-based, mobile-friendly evaluation tool to help fill this identified gap. The survey-based program creates a milestone-based evaluation, takes only a few minutes to complete, and easily collates the results in a graphic format creating an individualized “dashboard.” The dashboard is then used by both trainees and their evaluators as a feedback platform.

Results: With the implementation of the dashboard, educational leadership has noted an increase in the number of submitted evaluations of residents and the amount of face-to-face feedback given by attendings to residents. A post-implementation survey of the residents revealed that they found the dashboard-provided feedback more helpful than prior modes of feedback, although the number of evaluations was still too few.

Conclusion: The use of our feedback dashboard is useful to multiple targeted end-users, including general faculty evaluators, program leadership, and the residents themselves for gathering formative feedback that is specific and timely. This tool is adaptable and likely generalizable to other residency programs and specialties.