Summary: Despite advances in the treatment of asthma, optimization of symptom control remains an unmet need in many patients. These patients, labeled severe asthma, are responsible for a substantial fraction of the disease burden. In these patients, research is needed to define the cellular and molecular pathways contributing to disease which in large part are refractory to corticosteroid treatment. The causes of steroid‐resistant asthma are multifactorial and result from complex interactions of genetics, environmental factors, and innate and adaptive immunity. Adaptive immunity, addressed here, integrates the activities of distinct T‐cell subsets and by definition is dynamic and responsive to an ever‐changing environment and the influences of epigenetic modifications. These T‐cell subsets exhibit different susceptibilities to the actions of corticosteroids and, in some, corticosteroids enhance their functional activation. Moreover, these subsets are not fixed in lineage differentiation but can undergo transcriptional reprogramming in a bidirectional manner between protective and pathogenic effector states. Together, these factors contribute to asthma heterogeneity between patients but also in the same patient at different stages of their disease. Only by carefully defining mechanistic pathways, delineating their sensitivity to corticosteroids, and determining the balance between regulatory and effector pathways will precision medicine become a reality with selective and effective application of targeted therapies.

Purpose of review: This review addresses the growing understanding that a specific subset of patients with a respiratory disease, including asthma, chronic obstructive pulmonary disease (COPD), or bronchiectasis may have one thing in common: type 2 inflammation. In the era of personalized medicine, we need to refine clinical markers combined with molecular and cellular endotyping to improve patient outcomes. Recent findings: Recent literature reveals that type 2 markers such as blood eosinophils, fractional exhaled nitric oxide (FeNO), and immunglobulin E (IgE), can provide valuable insights into disease progression, exacerbation risk, and treatment response, but their stability remains to be investigated. Treating asthma and COPD patients with biologics to target IL-4/IL-13, IL-5, and alarmins have shown potential, although efficacy varied. In bronchiectasis, a subset of patients with type 2 inflammation may benefit from corticosteroid therapy, despite broader concerns regarding its use. Summary: This underscores the importance of improved disease endotyping to better characterize patients who may benefit from targeted therapies. In clinical practice, personalized treatment based on inflammatory profiles has been shown to improve outcomes in heterogeneous lung diseases. Future research needs to focus on validating reliable biomarkers and optimizing clinical trial designs to advance therapeutic strategies in respiratory diseases.

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8^−/−), with increased IL-6 levels in nTregs from CD8^−/− mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8^−/− mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8^−/− compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8^−/− mice. The predominant GT repeat in CD8^−/− nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis.

Rational: Steroid-insensitive type 2 cytokine-producing CD8 ⁺ T cells (Tc2) are enriched in patients with severe asthma and correlate with disease severity, highlighting their potential role as drivers of treatment-refractory disease. The molecular mechanisms governing their functional differentiation remain incompletely understood. Methods: Mouse CD8 ⁺ T cells were differentiated in vitro under type 1 or type 2 polarizing conditions. Genome-wide transcriptional and H3 histone acetylation profiles were analyzed using RNA sequencing and chromatin immunoprecipitation (ChIP) sequencing. Both were integrated to identify H3Ac-associated transcriptional programs. Functional consequences of pharmacologic inhibition of histone acetyltransferase (HAT) activity in Tc2 cells were assessed after adoptive transfer into allergen-sensitized CD8-deficient mice. In parallel, transcriptomic profiling of human CD8 ⁺ T cells from healthy individuals and steroid-resistant asthmatics was performed and integrated with the mouse Tc2 dataset to identify conserved regulatory pathways. Results: Tc1 and Tc2 differentiation were characterized by coordinated transcriptional remodeling with distinct type 2-associated networks emerging in response to IL-4 and T cell receptor stimulation including Il-24 , Cyp11a1 , and Il-13 . Integration of histone acetylation data and transcriptional networks identified condition-specific H3Ac-associated differentially-expressed genes (DEGs) and functional programs specific to Tc1 and Tc2 cells. While H3Ac-associated DEGs in Tc1 cells were linked predominantly to broader inflammatory and immune effector pathways, this integrative approach showed an enrichment of type 2 immune pathways in Tc2 cells. Pharmacologic modulation of HAT activity increased Tc2 cytokine responses and enhanced the pathogenic effects of Tc2 cells in vivo , resulting in heightened airway hyperresponsiveness and eosinophilic inflammation. Human CD8 ⁺ T cells from steroid-resistant asthmatics exhibited distinct transcriptional profiles compared with healthy individuals, including increased IL-13 expression. Cross-species integration revealed significant overlap between mouse Tc2 transcriptional signatures and gene networks in steroid-resistant asthmatics. Conclusion: These findings propose coordinated epigenetic and transcriptional remodeling as a central mechanism regulating functional differentiation of Tc2 cells. They further define shared molecular pathways linking CD8 ⁺ T cell programming to type 2 inflammation in severe asthma, providing insight into mechanisms that may contribute to persistent disease and therapeutic resistance.