PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection

Abstract

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV)infection During a lifetime the immune system is shaped by a history of infections. Prior infections with one pathogen may influence the severity of disease outcome to a subsequent infection with an unrelated pathogen, a phenomenon known as heterologous immunity (1). Enhanced immunopathology, which can be mediated by the activation of cross-reactive memory T cells, is one of the harmful consequences of heterologous immunity. For instance, it has been proposed during human infections that cross-reactive IAV-specific memory CD8 ϩ T cells can contribute to the induction of severe fulminant hepatitis during hepatitis C virus (HCV) infection and induction of acute infectious mononucleosis during Epstein-Barr virus (EBV) infection (2-4).Lung pathology is a common manifestation of respiratory infections and can vary greatly in severity in different individuals infected with the same pathogen. To investigate the role of altered immunopathology during heterologous immunity in a controlled experimental setting, we utilized a mouse model of IAV-immune mice infected with lymphocytic choriomeningitis virus (LCMV) (5). We initially chose these two viruses because they are phylogenetically unrelated and because they are naturally spread through infection of the respiratory mucosa and induce significant inflammation in the lung (6-11). Influenza virus is an extremely common respiratory pathogen in humans, and LCMV, which induces a flu-like illness in humans, is also a relatively common pathogen, with 5 to 14% of the general population being serologically positive (12). These IAV-immune mice infected with LCMV could develop acute lung injury similar to that seen in individuals that died during the H1N1 IAV pandemic in 1918, with enhanced bronchus-associated lymphoid tissue (BALT), mononuclear pneumonia, necrotizing bronchiolitis, vasculitis, and bronchiolization (13, 14) The severity of lung pathology varied among genetically identical mice from mild pneumonitis to severe mononuclear pneumonia, necrotizing bronchiolitis, and bronchiolization, an abnormal alveolar epithelial repair process considered premalignant and associated with idiopathic pulmonary fibrosis in humans. Although counterintuitive, severity of pathology did not directly correlate with LCMV titers. Instead, increased pathology was dependent on cross-reactive IAV-specific memory CD8 ϩ T cells (15). Disease severity was directly correlated with and could be predicted by the frequency of two IAV epitope-specific CD8 ϩ T-cell populations, PB1 703 and PA 224 , which are crossreactive with LCMV-GP 34 and -GP 276 , respectively. Eradication or functional ablation of these pathogenic populations of IAV-specific memory T cells using mutant viral strains, peptide-based tolerization strategies, or short-term anti-gamma interferon (IFN-␥) treatment prevented this pathology.Here, we continue to investigate this mouse model to determine if there are ot...

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

“…This suggests that the enhanced number of Tregs in chronically FV-infected mice did not alter mCMV clearance. Similar results were obtained in the models of acute LCMV infection of IAV-immune mice and chronic LCMV infection (14,28). As mentioned above, NK cells play a very important role in viral clearance in early mCMV infection of C57BL/6 mice, and even the strength of the mCMV-specific T cell response is partly controlled by NK cells (22)(23)(24)(25)(26).…”

“…ϩ T cell responses in mice sequentially infected with IAV and LCMV (14). Since nothing is known about the influence of virus-expanded Tregs in chronic viral infections on a primary unrelated infection, chronically FV-infected mice were superinfected with mCMV (FV/mCMV).…”

Vaccination and heterologous immunity: educating the immune system

“…26,34 In addition, T regulatory cells induced by IAV seem to play a role in dampening the overall T cell response to LCMV. 51 Interestingly, in both the IAV+LCMV and the LCMV+VACV systems, there is evidence that the cytokine responses early in infection as part of the innate responses are dramatically altered in immune versus naive mice during the acute viral infection. 26 This would suggest that prior infection could alter innate responses to a subsequent new pathogen and potentially play a role in the maturation of innate responses in the neonate.…”

“…40,47 Clear networks of crossreactive epitopes and patterns of beneficial or detrimental heterologous immunity have been defined in specific virus sequences in mouse models (Supplementary Figure 1). [24][25][26][27][28][29][30][31][32][33][34][48][49][50][51][52][53] For example, in the C57BL/6 mouse (H2 b ), CD8 T cell crossreactive epitopes have been defined between LCMV and Pichinde virus (PICV), LCMV and vaccinia virus (VACV), LCMV and murine cytomegalovirus (MCMV), LCMV and IAV, IAV and MCMV, and PICV and VACV, and complex networks of mouse or human T cell crossreactivity can exist between two viruses. 23,24,27,28,34,[54][55][56] Furthermore, structural studies on crossreactivity between LCMV and VACV epitopes can pinpoint the target of crossreactivity and render the OVA SIINFEKL epitope crossreactive with LCMV by an amino acid substitution.…”

Emerging Role of Regulatory T Cells in Heterologous Infections

“…In line with this using a heterologous infection model of persistent and non-persistent viral infections, it was shown for the first time that virus-expanded Treg cells could attenuate immune responses and influence induction of lung pathology during a subsequent unrelated non persistent virus infection (Kraft et al, 2013).…”