Conditioning of naive CD4(+) T cells for enhanced peripheral Foxp3 induction by nonspecific bystander inflammation.

Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation.

STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata.

Human asthma is a heterogeneous disease characterized by the expression of both Th2 and Th17 cytokines. In vitro and in vivo studies have shown a reciprocal regulation between Th2 and Th17 pathways, suggesting a potential induction of neutrophil-promoting Th17 inflammation in the absence of a Th2 response. Alternaria alternata is a clinically relevant allergen that is associated with severe and fatal asthma exacerbations. Exposure to A. alternata is characterized by a predominant Th2 response, but can also induce the production of factors associated with Th17 responses (e.g., CXCL8) from epithelial cells. Using a mouse model, we found that wild-type mice develop an eosinophilic Th2 airway disease in response to A. alternata exposure, whereas IL-4-, IL-13-, and STAT6-deficient mice exhibit a primarily neutrophilic response. Neutrophilic asthma in STAT6-/- mice was accompanied by elevated lung levels of TNF-α, CXCL1, CXCL2, and CXCL5, and was steroid resistant. Neutralization of Th17 signaling only partially reduced neutrophil numbers and total airway inflammation. Airway neutrophilia developed in RAG-deficient and CD4-depleted BALB/c mice, suggesting that the suppression of neutrophil responses is dependent on Th2 cytokine production by T cells and that airway neutrophilia is primarily an innate response to allergen. These results highlight the importance of combination therapies for treatment of asthma and establish a role for factors other than IL-17 as targets for neutrophilic asthma.

Cutting edge: De novo induction of functional Foxp3+ regulatory CD4 T cells in response to tissue-restricted self antigen.

Naive CD4 T cells can differentiate into a number of functional subsets in response to Ag, including Foxp3(+) induced regulatory T cells (iTregs). The in vivo development and function of iTregs has been primarily demonstrated in systems involving Ag encountered systemically or delivered via the intestinal mucosa. In this study, we demonstrate that de novo Foxp3 expression in naive CD4 T cells is a critical mechanism for establishing tolerance for a tissue-restricted neo-self Ag. Naive CD4 T cells lacking a functional Foxp3 gene cannot achieve tolerance, but can be suppressed in vivo in the presence of wild type naive CD4 T cells. Exposure to nonspecific inflammation during priming undermines tolerance through impaired Foxp3 induction, suggesting that the microenvironment also has a role. These data show that de novo Foxp3 expression is an integral component of establishing and maintaining tolerance among naive peripheral CD4 T cells.