miR-23~27~24 regulates TFH cells through targeting multiple genes including TOX, a key transcription factor for TFH cell biology.

During thymocyte development, medullary thymic epithelial cells (mTECs) provide appropriate instructive cues in the thymic microenvironment for not only negative selection but also the generation of regulatory T (T reg) cells. Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGFβ signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155–TGFβ axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.

Hyponatremia post-neurosurgical intervention can be dangerous and potentially life-threatening. Two of its most common causes are cerebral salt wasting (CSW) and syndrome of inappropriate anti-diuretic hormone release (SIADH). CSW is proposed to be secondary not only to the elevated levels of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) but inhibition of steroidogenesis in the zona glomerulosa of the adrenal cortex, thus resulting in mineralocorticoid deficiency. We present a two-year-old male who had developed acute hyponatremia secondary to CSW on post-operative day two after a sub-total resection of a low-grade juvenile pilocytic astrocytoma (WHO grade I). Fludrocortisone was successfully used to manage the refractory hyponatremia and alleviated the need to use very large amounts of oral sodium supplementation.

MicroRNA-155 (miR-155) is a small non-coding RNA highly upregulated in regulatory T (Treg) cells, an immune cell population specialized in maintaining immunological tolerance. While the importance of miR-155 in conferring Treg cell competitive fitness has been well established, how miR-155 regulates Treg cell development remains unknown. By taking cell-type specific gene targeting approaches, we demonstrate that miR-155 controls thymic Treg (tTreg) cell differentiation in both T cell-intrinsic and -extrinsic manners. Specifically, we show that mature CD80hiMHCIIhi medullary thymic epithelial cells (mTECs) crucial for the generation of tTreg cells express high levels of miR-155, where TEC-specific deletion of miR-155 diminishes this population and impairs tTreg cell development. Previously, the size of the mature mTEC compartment has been shown to be regulated by TGF-β signaling. Here, our results identify SMAD3, a key molecule downstream of TGF-β signaling, is targeted by miR-155 in mTECs. Thus, we propose a miR-155-SMAD3-TGF-β axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tTreg cells.

Background There is a growing awareness surrounding gender diversity and the critical need for more robust research and evidence to guide gender-affirming healthcare, including gender-affirming hormone therapy (GAHT). Research priorities are often determined by clinicians and researchers; we lack data about the transgender and gender diverse (TGD) community's priorities for research. Objective To determine the research priorities of adult TGD patients who receive care at a multidisciplinary gender-affirming clinical program at a tertiary academic medical center. Design/Methods IRB-approved electronic surveys were sent to 719 patients who sought care from the program in the last year. Participants were asked to rank research topics within six domains based on the importance of the topic to their care: 1) care access/utilization within the program, 2) GAHT impacts on the body, 3) GAHT concerns/potential adverse effects, 4) gender-affirming surgeries, 5) mental health, and 6) navigating healthcare/work/school, with 6-7 choices in each category, including a free text option to fill out their own research priority. Results 135 individuals consented and responded to the survey (19% response rate). Almost half were aged 18-29 years (45%), and several were aged 50 years or older (16%). Nearly all identified as white (92%). Participants were able to check more than one response for these demographics: feminine gender identity (55%; inclusive of female, transgender female, and/or transfeminine); masculine gender identity (37%; inclusive of male, transgender male, and/or transmasculine), nonbinary (25%), and/or something else (25%). The top two research priorities (by % respondents ranking the topic as most important) within each of the six domains were: 1) care access/utilization within the program: have insurance coverage for gender-affirming care (66%), have gender-affirming surgery (33%); 2) GAHT impacts on the body: overall feminizing/masculinizing effects (81%), mental health/mood (69%); 3) GAHT concerns/potential adverse effects: heart health (54%), blood clots/stroke (47%); 4) gender-affirming surgeries: common complications (57%), post-op sexual function/pleasure (51%); 5) mental health: GAHT (59%) and surgeries (46%) impact on suicide risk; and 6) navigating healthcare/work/school: barriers to accessing care (61%), training community providers (58%). Fertility was ranked as the least important research priority. Research on the discontinuation of gender-affirming interventions and regret in getting gender-affirming surgery were also ranked as low priorities. Conclusions TGD adults receiving care at a tertiary academic medical center ranked GAHT's effects on overall feminization/masculinization, mental health/suicide risk, common surgery complications, and cardiovascular health as top research priorities. They also indicated a desire for more research on barriers to accessing care, especially insurance coverage and provider education. Compared to other topics, fertility was ranked as the least important research priority. The TGD community's research priorities should be used to inform TGD health funding and researcher priorities to ensure that research evidence leads to improvements in patient-centered gender-affirming care. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.