Faculty Bibliography

Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c⁺CD64⁺ double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.

BACKGROUND & AIMS/OBJECTIVE:Several studies have shown that signaling via the interleukin 23 (IL23) receptor is required for development of colitis. We studied the roles of IL23, dietary factors, alterations to the microbiota, and T cells in development and progression of colitis in mice. METHODS:mice, and T-cell receptor sequences were determined. RESULTS:mice without colitis (fed the 5053 diet), due to expansion of dominant T-cell clones. CONCLUSIONS:T cells that becomes activated in response to dietary changes and alterations to the intestinal microbiota. The results indicate that alterations in the diet, intestinal microbiota, and IL23 signaling can contribute to pathogenesis of inflammatory bowel disease.

The originally published version of this Article contained errors in Fig. 4 that were introduced during the production process. In panel c, the two uppermost labels 'IgE spleen' and 'IgE BM' incorrectly read 'IgG1 spleen' and 'IgE1 BM', respectively. These errors have now been corrected in both the PDF and HTML versions of the Article.

It has been shown that dominant tolerance, namely in transplantation, requires Foxp3+ regulatory T cells. Although most tolerance-inducing regimens rely on regulatory T cells, we found that induction of tolerance to proteins in aluminum hydroxide can be achieved in Foxp3-deficient mice using nondepleting anti-CD4 Abs. This type of tolerance is Ag specific, and tolerant mice retain immune competence to respond to unrelated Ags. We demonstrated with chicken OVA-specific TCR-transgenic mice that the same tolerizing protocol (CD4 blockade) and the same target Ag (OVA) achieves Foxp3-dependent transplantation tolerance to OVA-expressing skin grafts, but Foxp3-independent tolerance when the Ag is provided as OVA-aluminum hydroxide. In the latter case, we found that tolerance induction triggered recessive mechanisms leading to elimination of effector cells and, simultaneously, a dominant mechanism associated with the emergence of an anergic and regulatory CTLA-4+IL-2lowFoxp3- T cell population, where the tolerance state is IL-10 dependent. Such Foxp3-independent mechanisms can improve the efficacy of tolerance-inducing protocols.

The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory. IgE germinal centre cells are transient, most IgE cells are plasma cells, and high affinity IgE is produced by the switching of IgG1 cells to IgE. Here we investigate the function of subsets of IgG1 memory B cells in IgE production and find that two subsets of IgG1 memory B cells, CD80+CD73+ and CD80-CD73-, contribute distinctively to the repertoires of high affinity pathogenic IgE and low affinity non-pathogenic IgE. Furthermore, repertoire analysis indicates that high affinity IgE and IgG1 plasma cells differentiate from rare CD80+CD73+ high affinity memory clones without undergoing further mutagenesis. By identifying the cellular origin of high affinity IgE and the clonal selection of high affinity memory B cells into the plasma cell fate, our findings provide fundamental insights into the pathogenesis of allergies, and on the mechanisms of antibody production in memory B cell responses.IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.

Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-alpha-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-alpha as potential therapeutic targets for preventing infection-induced cognitive dysfunction.

The production of IL-21 by T follicular helper (Tfh) cells is vital in driving the germinal centre reaction and high affinity antibody formation. However, the degree of Tfh cell heterogeneity and function is not fully understood. We used a novel IL-21eGFP reporter mouse strain to analyze the diversity and role of Tfh cells. Through the analysis of GFP expression in lymphoid organs of IL-21eGFP mice, we identified a subpopulation of GFP(+), high IL-21 producing Tfh cells present only in Peyer's Patches. GFP(+)Tfh cells were found to be polyclonal and related to GFP(-)Tfh cells of Peyer's Patches in TCR repertoire composition and overall gene expression. Studies on the mechanisms of induction of GFP(+)Tfh cells demonstrated that they required the intestinal microbiota and a diverse repertoire of CD4(+) T cells and B cells. Importantly, ablation of GFP(+) cells resulted in a reduced frequency of Peyer's Patches IgG1 and germinal center B cells in addition to small but significant shifts in gut microbiome composition. Our work highlights the diversity among IL-21 producing CD4(+) Tfh cells, and the interrelationship between the intestinal bacteria and Tfh cell responses in the gut.

Foxp3+ regulatory T cells in peripheral tissues (pTregs) are instrumental in limiting inflammatory responses to non-self antigens. Within the intestine, pTregs are located primarily in the lamina propria, while intraepithelial CD4+ T cells (CD4IELs), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we show distinct cell dynamics of intestinal Tregs and CD4IELs Upon migration to the epithelium, Tregs lose Foxp3 and convert to CD4IELs in a microbiota-dependent fashion, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pTregs and CD4IELs perform complementary roles in the regulation of intestinal inflammation. These results reveal intra-tissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine.