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1.  Id2 reinforces TH1 cell differentiation and inhibits E2A to repress TFH cell differentiation 
Nature immunology  2016;17(7):834-843.
Differentiation of T helper (TH) effector subsets is critical for host protection. E protein transcription factors and Id proteins are important arbiters of T cell development, but their role in differentiation of TH1 and TFH cells is not well understood. TH1 cells showed robust Id2 expression compared to TFH cells, and RNAi depletion of Id2 increased TFH cell frequencies. Further, TH1 cell differentiation was blocked by Id2 deficiency, leading to E protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired generation of TH1 cells following Toxoplasma gondii infection. The TFH-defining transcriptional repressor Bcl6 bound the Id2 locus, providing a mechanism for the bimodal Id2 expression and reciprocal development of TH1 and TFH cell fates.
PMCID: PMC4915968  PMID: 27213691
2.  CD8 T cells utilize IFN-γ to protect against the lethal effects of a respiratory poxvirus infection 
CD8 T cells are a key component of immunity to many viral infections. They achieve this through utilizing an array of effector mechanisms, but precisely which component/s are required for protection against a respiratory Orthopoxvirus infection remains unclear. Using a model of respiratory vaccinia virus (VACV) infection in mice, we could specifically determine the relative contribution of perforin, TRAIL, and IFN-γ mediated pathways in protection against virus induced morbidity and mortality. Unexpectedly, we observed that protection against death was mediated by IFN-γ without any involvement of the perforin or TRAIL-dependent pathways. IFN-γ mRNA and protein levels in the lung peaked between days 3 and 6 post infection. This enhanced response coincided with the emergence of virus-specific CD8 T cells in the lung and the cessation of weight loss. Transfer experiments indicated that CD8 T cell autonomous expression of IFN-γ restricts virus induced lung pathology, dissemination to visceral tissues, and is necessary for clearance of virus. Most significantly, we show that CD8 T cell derived IFN-γ is sufficient to protect mice in the absence of CD4 and B-lymphocytes. Thus our findings reveal a previously unappreciated mechanism by which effector CD8 T cells afford protection against a highly virulent respiratory Orthopoxvirus infection.
PMCID: PMC4036466  PMID: 24748494
CD8 T cells; interferon gamma; Vaccinia Virus; Poxviruses; Lung
3.  Parenteral fluids do not affect pulmonary immune responses to influenza or susceptibility to secondary bacterial pneumonia in mice 
Animal models of viral respiratory disease often use weight loss as a marker of disease severity; however, this may relate to dehydration and malnutrition that would be corrected clinically. We tested whether parenteral fluid therapy improved weight loss from influenza infection. BALB/c and C57BL/6 mice were infected with A/X31 (H3N2) influenza and randomized to intraperitoneal fluid therapy. Blood glucose was also measured post‐viral infection on day 3 and 6 in BALB/c mice and on day 6 in C57BL/6 mice. Parenteral fluids did not alter weight loss or the immunological response to infection, and glucose levels were not abnormal.
PMCID: PMC4634233  PMID: 23279978
Glucose; influenza; rehydration
4.  CD8 T cells are essential for recovery from a respiratory vaccinia virus infection 
The precise immune components required for protection against a respiratory Orthopoxviridae infection, such as human smallpox or monkey pox, remain to be fully identified. In this study we utilized the virulent Western Reserve strain of vaccinia virus (VACV-WR) to model a primary respiratory Orthopoxviridae infection. Naïve mice infected with VACV-WR mounted an early CD8 T cell response, directed against dominant and subdominant VACV-WR antigens, followed by a CD4 T cell and immunoglobulin (Ig) response. In contrast to other VACV-WR infection models that highlight the critical requirement for CD4 T cells and Ig, we found that only mice deficient in CD8 T cells presented with severe cachexia, pulmonary inflammation, viral dissemination and 100 % mortality. Depletion of CD8 T cells at specified times throughout infection highlighted that CD8 T cells perform their critical function between days four and six post infection and that their protective requirement is critically dictated by initial viral load and virulence. Finally, the capacity of adoptively transferred naïve CD8 T cells to protect RAG -/- mice against a lethal VACV-WR infection demonstrated that CD8 T cells are both necessary and sufficient in protecting against a primary VACV-WR infection of the respiratory tract.
PMCID: PMC3496758  PMID: 22826318
CD8 T cells; Antibodies; Vaccinia Virus; Poxviruses; Lung
5.  OX40:OX40L axis: emerging targets for improving poxvirus-based CD8+ T-cell vaccines against respiratory viruses 
Immunological reviews  2011;244(1):149-168.
The human respiratory tract is the entry point for over 200 known viruses that collectively contribute to millions of annual deaths worldwide. Consequently the World Health Organization has designated respiratory viral infections as a priority for vaccine development. Despite enormous advances in understanding the attributes of a protective mucosal antiviral immune response, current vaccines continue to fail in effectively generating long-lived protective CD8+ T-cell immunity. To date, the majority of licensed human vaccines afford protection against infectious pathogens through the generation of specific immunoglobulin responses. In recent years, the selective manipulation of specific costimulatory pathways, which are critical in regulating T-cell-mediated immune responses, has generated increasing interest. Impressive results in animal models have shown that the tumor necrosis factor receptor (TNFR) family member OX40 (CD134) and its binding partner OX40L (CD252) are key costimulatory molecules involved in the generation of protective CD8+ T-cell responses at mucosal surfaces such as the lung. In this review, we highlight these new findings with a particular emphasis on their potential as immunological adjuvants to enhance poxvirus-based CD8+ T-cell vaccines.
PMCID: PMC3422077  PMID: 22017437
CD8+ T cells; vaccines; influenza; poxviruses; lung; OX40/OX40L
6.  Lowering the Threshold of Lung Innate Immune Cell Activation Alters Susceptibility to Secondary Bacterial Superinfection 
The Journal of Infectious Diseases  2011;204(7):1086-1094.
Background. Previous studies have shown that the interaction of CD200R, a myeloid inhibitory receptor, with its ligand, CD200, is critical in the control of innate immune activation in the lung.
Methods and Results. Using a mouse model of bacterial superinfection following influenza, we show that an absence of CD200R (a negative regulator highly expressed by macrophages and dendritic cells), restricts commensal and exogenous bacterial invasiveness and completely prevents the mortality observed in wild-type mice. This benefit is due to a heightened innate immune response to influenza virus in cd200r knockout mice that limits immune pathogenesis and viral load. In wild-type mice, apoptotic cells expressing CD200 that we believe contribute to the suppressed innate immune response to bacteria dominate during the resolution phase of influenza-induced inflammation. We also show for the first time the presence of a variety of previously unidentified bacterial species in the lower airways that are significantly adjusted by influenza virus infection and may contribute to the pathophysiology of disease.
Conclusions. The interaction of CD200 with CD200R therefore contributes to the hyporesponsive innate immune state following influenza virus infection that predisposes to secondary bacterial infection, a phenomenon that has the potential for immune modulation.
PMCID: PMC3164429  PMID: 21881124
8.  Respiratory Infections 
Although the outcome of respiratory infection alters with age, nutritional status, and immunologic competence, there is a growing body of evidence that we all develop a unique but subtle inflammatory profile. This uniqueness is determined by the sequence of infections or antigenic insults encountered that permanently mold our lungs through experience. This experience and learning process forms the basis of immunologic memory that is attributed to the acquired immune system. But what happens if the pathogen is not homologous to any preceding it? In the absence of cross-specific acquired immunity, one would expect a response similar to that of a subject who had never been infected with anything before. It is now clear that this is not the case. Prior inflammation in the respiratory tract alters immunity and pathology to subsequent infections even when they are antigenically distinct. Furthermore, the influence of the first infection is long lasting, not dependent on the presence of T and B cells, and effective against disparate pathogen combinations. We have used the term “innate imprinting” to explain this phenomenon, although innate education may be a closer description. This educational process, by sequential waves of infection, may be beneficial, as shown for successive viral infections, or significantly worse, as illustrated by the increased susceptibly to life-threatening bacterial pneumonia in patients infected with seasonal and pandemic influenza. We now examine what these long-term changes involve, the likely cell populations affected, and what this means to those studying inflammatory disorders in the lung.
PMCID: PMC2647650  PMID: 18073393
lung inflammation; heterologous immunity; respiratory tract; influenza; innate immunity
9.  Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection 
The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for ∼35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-κB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.
PMCID: PMC2271005  PMID: 18227219

Results 1-9 (9)