During the development of immune responses to pathogens, self-antigens, or environmental allergens, naive CD4(+) T cells differentiate into subsets of effector cells including Th1, Th2, and Th17 cells. The differentiation into these subsets is controlled by specific transcription factors. The activity of these effector cells is limited by nTregs and iTregs, whose differentiation and maintenance are dependent on the transcription factor Foxp3. The regulation of autoimmune diseases mediated by Th1 and Th17 cells by Tregs has been studied and reviewed extensively. However, much less has been presented about the interplay between Tregs and Th2 cells and their contribution to allergic disease. In this perspective, we discuss the regulation of Th2 cells by Tregs and vice versa, focusing on the interplay between the IL-4-activated STAT6/GATA3 pathway and Foxp3.

Insulin Receptor Substrate (IRS)-2 is an adaptor protein that becomes tyrosine phosphorylated in response to IL-4 and IL-13 resulting in activation of the PI-3′ kinase/Akt pathway. While the contribution of IL-4 and IL-13 to allergic lung inflammation has been studied extensively, the functional significance of the IRS2 pathway is unclear. To examine the role of IRS2 in allergic disease, we evaluated responses in IRS2-deficient mice. Deficiency of IRS2 resulted in a substantial increase in expression of a subset of genes associated with alternatively activated macrophages (AAM) in response to IL-4 or IL-13 in vitro. Moreover, IRS2+/− and IRS2−/− mice developed enhanced pulmonary inflammation, accumulation of eosinophils and AAM, and airway and vascular remodeling upon allergen stimulation in comparison to IRS2+/+ mice; this enhanced response was in part macrophage intrinsic. Loss of IRS2 led to greater phosphorylation of Akt and ribosomal S6 protein in the basal state and upon IL-4 stimulation. Thus, we identify a critical negative regulatory loop downstream of IRS2, demonstrating a previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling.

STAT6 plays a central role in IL-4-mediated allergic responses. Several studies indicate that regulatory T cells (Treg) can be modulated by IL-4 in vitro. We previously showed that STAT6−/− mice are highly resistant to allergic lung inflammation even when wild type Th2 effectors were provided and that they have increased numbers of Tregs. However, the role of STAT6 in modulating Tregs in vivo during allergic lung inflammation has not been thoroughly investigated. To investigate Treg and STAT6 interaction during allergic inflammation, STAT6−/−, STAT6×RAG2−/− and RAG2−/− mice were subjected to OVA sensitization and challenge following adoptive transfer of OVA-specific, wild type Th2 effectors with or without prior Treg depletion/ inactivation using anti-CD25 (PC61). As expected, STAT6−/− mice were highly resistant to airway inflammation and remodeling. In contrast, allergic lung inflammation was partially restored in STAT6−/− mice treated with PC61 to levels observed in STAT6×RAG2−/− mice. In some cases, STAT6×RAG2−/− mice were also given natural (n) Tregs along with Th2 effectors. Adoptive transfer of nTregs caused a substantial reduction in BAL eosinophil composition and suppressed airway remodeling and T cell migration into the lung in STAT6×RAG2−/− mice to levels comparable to those in STAT6−/− mice. These results demonstrate the STAT6-dependent suppression of Tregs in vivo in order to promote allergic airway inflammation.

Respiratory rate (RR) is important in many patient care settings; however, direct observation of RR is cumbersome and often inaccurate, and electrocardiogram-derived RR (RR) is unreliable. We asked how data derived from the first 15 min of RR recording after trauma center admission using a novel acoustic sensor (RR) would compare to RR and to end-tidal carbon dioxide-based RR ([Formula: see text]) from intubated patients, the "gold standard" in predicting life-saving interventions in unstable trauma patients. In a convenience sample subset of trauma patients admitted to our Level 1 trauma center, enrolled in the ONPOINT study, and monitored with RR, some of whom also had [Formula: see text] data, we collected RRa using an adhesive sensor with an integrated acoustic transducer (Masimo RRa™). Using Bland-Altman analysis of area under the receiver operating characteristic (AUROC) curves, we compared the first 15 min of continuous RRa and RR to [Formula: see text] and assessed the performance of these three parameters compared to the Revised Trauma Score (RTS) in predicting blood transfusion 3, 6, and 12 h after admission. Of the 1200 patients enrolled in ONPOINT from December 2011 to May 2013, 1191 had RR data recorded in the first 15 min, 358 had acoustic monitoring, and 14 of the latter also had [Formula: see text]. The three groups did not differ demographically or in mechanism of injury. RR showed less bias (0.8 vs. 6.9) and better agreement than RR when compared to [Formula: see text]. At [Formula: see text] 10-29 breaths per minute, RR was more likely to be the same as [Formula: see text] and assign the same RTS. In predicting transfusion, features derived from RR and RR gave AUROCs 0.59-0.66 but with true positive rate 0.70-0.89. RR monitoring is a non-invasive option to glean valid RR data to assist clinical decision making and could contribute to prediction models in non-intubated unstable trauma patients.

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