Summary STAT3 transcription factor signaling in specific T helper cell differentiation have been well described, whereas the broader roles for STAT3 in lymphocyte memory are less clear. Patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry dominant negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4+ and CD8+ T cells compared to healthy controls. Naïve T cells from AD-HIES patients had lower expression of memory-related transcription factors BCL6 and SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses.

Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1α. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10−/− B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells—perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis—identifying a strategy that appears to be conserved between at least EBV and MHV68.

Background Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.

Recent evidence from the study of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus supports a model in which terminal differentiation of B cells to plasma cells leads to virus reactivation. Here we address the role of Blimp-1, the master transcriptional regulator of plasma cell differentiation, in murine gammaherpesvirus 68 (MHV68) latency and reactivation. Blimp-1 expression in infected cells was dispensable for acute virus replication in the lung following intranasal inoculation and in the spleen following intraperitoneal inoculation with MHV68. However, we observed a role for Blimp-1 in both the establishment of latency and reactivation from latency in vivo. Additionally, plasma cell-deficient mice also exhibited a significant defect in the establishment of latency in the spleen, as well as reactivation from latency, similar to mice that lacked Blimp-1 only in MHV68-infected cells. In the absence of plasma cells, MHV68 infection failed to elicit a strong germinal center response and fewer B cells in the germinal center were MHV68 infected. Notably, the absence of a functional Blimp-1 gene only in MHV68-infected cells led to a decrease in both B-cell and CD4؉ T-cell responses during the establishment of latency. Finally, Blimp-1 expression in infected cells played a critical role in the maintenance of both MHV68 latency in the spleen and antibody responses to MHV68. Together, these studies support a model wherein episodic Blimp-1-mediated plasma cell differentiation leads to MHV68 reactivation, which serves to both renew the latency reservoirs and stimulate long-lived plasma cells to secrete virus-specific antibody.