Publications

Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal a novel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease.

Coccidioidomycosis ('Valley Fever'), caused by the inhalation of the fungus Coccidioides, remains a recalcitrant health problem in large parts of California. The incidence and severity of the disease continues to rise in many parts of the state. In this manuscript, we highlight unanswered questions about the disease. Specifically, the extent of disease burden, genetic determinants of host susceptibility, diagnostic and treatment guidelines, natural reservoirs of the pathogens, antifungal drug resistance, and fungal determinants of mild or severe disease are all areas awaiting in depth investigations. We also recommend establishment of a California Coccidioidomycosis Registry to improve clinical care and translational research.

It is well understood that antigen-presenting cells (APCs) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human tumor biopsies, we have delineated the intratumoral dendritic cell (DC) populations as distinct from macrophage populations. Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types.

Food-producing livelihoods have the potential to improve food security and nutrition through direct consumption or indirectly through income. To better understand these pathways, we examined if fishing households ate more fish and had higher food security than non-fishing households around Lake Victoria, Kenya. In 2010, we randomly sampled 111 households containing 583 individuals for a cross-sectional household survey in a rural fishing community. We modeled the associations between fish consumption and food security and fishing household status, as well as socio-economic variables (asset index, monthly income, household size) for all households and also for a subset of households with adult male household members (76% of households). Participating in fishing as a livelihood was not associated with household fish consumption or food security. Higher household fish consumption was associated with higher household income and food security, and was weakly associated with lower household morbidity. Household food security was associated with higher incomes and asset index scores. Our results suggest socioeconomic factors may be more important than participation in food-producing livelihoods for predicting household consumption of high quality foods.

IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans.