Factors Influencing Career Choice of Allergy and Immunology Fellows-in-Training: A Work Group Report of the AAAAI Program Directors Assembly Executive Committee.

BACKGROUND: As the burden of allergic and immunologic disease continues to increase, there is increased demand for a larger Allergy and Immunology (AI) subspecialty workforce. The field must prioritize the expansion of our workforce and the recruitment of exceptional and diverse trainees to ensure the vitality of the specialty. Although the AI fellowship match has traditionally been competitive, recent trends in fellowship applications have demonstrated fewer applicants per fellowship position. This trend has made recruitment a priority on the agenda of the national AI societies. OBJECTIVE: To elucidate key factors influencing the decision to choose the field of AI by querying fellows-in-training. METHODS: A survey was created and distributed yearly to fellows-in-training from 2017 to 2021 to identify factors influencing a career choice in AI. RESULTS: Approximately 59% of respondents rotated with AI in residency and 35% in both medical school and residency. Most respondents reported having a mentor in the field before fellowship, and many had their first exposures to AI during medical school (40%) or residency (32%). Most respondents decided to pursue AI during residency. The most common factors that influenced the decision to pursue AI were work/life balance, clinical aspects of the field, mentorship, and research opportunities. CONCLUSIONS: Our data suggest that the decision to pursue a career in AI often occurs during residency training and is motivated primarily by work/life balance, clinical aspects of the field, and clinician mentorship. Our survey results could provide guidance to AI training programs on strategies to recruit exceptional and diverse trainees.

Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function.

Perforin-mediated lymphocyte cytotoxicity is critical for pathogen elimination and immune homeostasis. Perforin disruption of target cell membranes is hypothesized to require binding of a calcium-dependent, lipid-inserting, C2 domain. In a family affected by hemophagocytic lymphohistiocytosis, a severe inflammatory disorder caused by perforin deficiency, we identified 2 amino acid substitutions in the perforin C2 domain: T435M, a previously identified mutant with disputed pathogenicity, and Y438C, a novel substitution. Using biophysical modeling, we predicted that the T435M substitution, but not Y438C, would interfere with calcium binding and thus cytotoxic function. The capacity for cytotoxic function was tested after expression of the variant perforins in rat basophilic leukemia cells and murine cytotoxic T lymphocytes. As predicted, cells transduced with perforin-T435M lacked cytotoxicity, but those expressing perforin-Y438C displayed intact cytotoxic function. Using novel antibody-capture and liposome-binding assays, we found that both mutant perforins were secreted; however, only nonmutated and Y438C-substituted perforins were capable of calcium-dependent lipid binding. In addition, we found that perforin-Y438C was capable of mediating cytotoxicity without apparent proteolytic maturation. This study clearly demonstrates the pathogenicity of the T435M mutation and illustrates, for the first time, the critical role of the human perforin C2 domain for calcium-dependent, cytotoxic function.