Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response.

Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8-/- mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8-/-CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1ß that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1ß, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease.

Regulatory T cells differ from conventional CD4+ T cells in their recirculatory behavior and lymph node transit times.

Regulatory T cells (Tregs) continuously suppress autoreactive immune responses within tissues to prevent autoimmunity, yet the recirculatory behavior of Tregs between and within tissues enabling the maintenance of peripheral tolerance remains incompletely defined. Here, we quantified homing efficiency to and the dwell time of Tregs within secondary lymphoid organs (SLOs) and used intravital two-photon microscopy to measure Treg surveillance behavior of dendritic cells. Tregs homed substantially less efficiently to SLOs compared with conventional CD4+ T cells (Tconvs), despite similar expression of homing receptors. Tregs remained on average 2-3 times longer within the LN than Tconvs before exiting, and retained Tregs differed from recirculating Tregs in phenotype, motility and interaction duration with dendritic cells. Taken together, these data revealed fundamental differences in Treg versus conventional T cell in vivo recirculation and migration behaviors, identified a Treg population with prolonged LN dwell time, and provided quantitative insight into their spatiotemporal behavior within LNs.

Experiences of Participants During In Situ Simulation With a Learner Present.

BACKGROUND: While in situ simulation (ISS) provides robust value for health care teams, it is less clear how medical learners affect the experiences of other participants. METHODS: This was a single-center qualitative analysis of a community hospital's emergency department ISS program that included medical learners (medical students, family and emergency medicine residents). Focus groups were conducted before and after with nurses, staff physicians, and resident physicians. Phenomenologic analysis using a constructivist framework was used to examine themes. RESULTS: Fifty-two ISSs were held from February 2019 to March 2020. Of those simulations, 36 had learners present. Positive effects included creating an open learning environment and offering staff physicians a safe teaching space. Negative effects arose when objectives of ISS were highly team based or latent safety threat (LST) focused. All groups thought learners added value to ISS. CONCLUSION: Thought should be given to ISS objectives when considering how learners affect other participants. When including learners, review objectives, clarify expectations in prebriefing, and ensure that debriefing begins with LSTs and process objectives before diving into medical objectives. This study provides insight into the effect of medical learners on ISS.