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SARS-CoV-2 infection has claimed just over 1.1 million lives in the US since 2020. Globally, the SARS-CoV-2 respiratory infection spread to 771 million people and caused mortality in 6.9 million individuals to date. Much of the early literature showed that SARS-CoV-2 immunity was defective in the early stages of the pandemic, leading to heightened and, sometimes, chronic inflammatory responses in the lungs. This lung-associated ‘cytokine storm’ or ‘cytokine release syndrome’ led to the need for oxygen supplementation, respiratory distress syndrome, and mechanical ventilation in a relatively high number of people. In this study, we evaluated circulating PBMC from non-hospitalized, male and female, COVID-19+ individuals over the course of infection, from the day of diagnosis (day 0) to one-week post diagnosis (day 7), and finally 4 weeks after diagnosis (day 28). In our early studies, we included hospitalized and critically care patient PBMC; however, most of these individuals were lymphopenic, which limited our assessments of their immune integrity. We chose a panel of 30 interferon-stimulated genes (ISG) to evaluate by PCR and completed flow analysis for immune populations present in those PBMC. Lastly, we assessed immune activation by stimulating PBMC with common TLR ligands. We identified changes in innate cells, primarily the innate lymphoid cells (ILC, NK cells) and adaptive immune cells (CD4+ and CD8+ T cells) over this time course of infection. We found that the TLR-7 agonist, Resiquimod, and the TLR-4 ligand, LPS, induced significantly better IFNα and IFNγ responses in the later phase (day 28) of SARS-CoV-2 infection in those non-hospitalized COVID-19+ individuals as compared to early infection (day 0 and day 7). We concluded that TLR-7 and TLR-4 agonists may be effective adjuvants in COVID-19 vaccines for mounting immunity that is long-lasting against SARS-CoV-2 infection.

Asthma is a chronic airway inflammatory disorder that demonstrates a strong clinical bias in females of reproductive age. In this study we evaluated group 2 innate lymphoid cells (ILC2) that play a now well-defined role in allergy and asthma. ILC2 are rare immune cells that demonstrate a strong activation bias in females compared to males in both mice and humans. We hypothesized that ILC2 would be highly activated in people with asthma as compared to healthy, sex-matched controls. Subjects with asthma were identified by medical records searching and confirmed through pre-clinic interviews regarding asthma diagnosis. Additional demographic and clinical data were collected from study questionnaires or retrospective chart review. Correlations were determined between immune activation and hormone levels for each study participant regardless of healthy or asthma status. Results showed that within the asthma groups, female Veterans had higher circulating blood neutrophils compared to males, and males had higher eosinophils compared to females by complete blood cell count. ILC2 trended upwards in male Veterans with asthma compared to female Veterans with asthma (p = 0.086). Females with asthma had a marked reduction in CRTH2+ ILC2 in comparison to healthy female controls. The numbers of ILC2 in correlation to ovarian hormones were determined to show a significant inverse correlation with estrogen levels and ILC2 suggesting that estrogen may suppress ILC2 abundance in circulation. Additional studies are necessary to determine whether this estrogen-effect extends to the lung and airways of people with asthma.

Asthma affects over 300 million people worldwide, with increasing rates annually. Males have higher asthma prevalence in adolescence, while females exhibit higher rates in adulthood. Reduced mucosal‐associated invariant T (MAIT) cells are found in severe asthmatic airway disease. We hypothesize MAIT cells modulate airway inflammation and are regulated by sex hormones through their cognate hormone receptors. We compared circulating MAIT cells and ex vivo MAIT cell activation with MR‐1 ligand in controls and asthmatic individuals. MAIT cells were significantly lower in asthmatic males and females compared to healthy controls. MAIT cells derived from male and female asthma patients exhibited higher levels of estrogen receptors (ERs) than those from sex‐matched healthy controls, and ex vivo treatment with estrogen significantly decreased IFN‐γ production in asthmatics. Estrogen treatment did not reduce IFN‐γ in MAIT cells from healthy individuals. To explore the effect of estrogen on MAIT cells, we used the murine Alternaria alternata challenge model. Adoptive transfer of G‐protein coupled ER (GPER‐1) antagonist (G36)‐treated MAIT cells into Rag1 knockout mice (Rag1 −/− ) increased A. alternata ‐induced inflammation compared to those receiving MAIT cells without GPER‐1 blockade. These findings suggest GPER‐1 as a novel target to reduce airway disease in the asthmatic population.

Type 2 immunity is initiated through a synergistic response between innate and adaptive immune cells to facilitate host-pathogen defense and wound repair, yet aberrant responses can contribute to chronic inflammation and allergic disease. CD4 type 2 helper T (Th2) cells facilitate the adaptive immune response through the secretion of cytokines such as IL-4, IL-5, and IL-13. While the Th2 program is governed by the transcription factor GATA3, less is known about regulators that fine-tune the Th2 cytokine response. We used a proximity labeling system to map proteins associated with the transcriptional co-regulator OCA-B, encoded by , in T cells. We used a series of genomic, biochemical and immunological assays to probe the interaction with one particular hit from the screen. We find that OCA-B indirectly associates with GATA3. ChIP-seq analysis reveals coenrichment of Gata3 and the transcription factor Oct1, a partner protein of OCA-B, at genomic locations responsible for the Th2 program including , and . DNA binding data using recombinant proteins and reporter data using T cell lines are consistent with a model in which OCA-B restricts transcription at the Th2 locus control region and subsequent IL-4 and IL-13 secretion. Finally, in an papain allergy model we show OCA-B expression in T cells limits the frequency of T cells within the lung. These findings shown that OCA-B helps restrict Th2 function at least in part through communication with GATA3.