Anti–IFN-γ and Peptide-Tolerization Therapies Inhibit Acute Lung Injury Induced by Cross-Reactive Influenza A–Specific Memory T Cells

Abstract

Viral infections have variable outcomes with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with IAV and in memory-phase challenged with LCMV, which we show here to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients that died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and -PA224-specific responses, which crossreacted with LCMV-GP34 and -GP276, respectively. Eradication or functional ablation of these pathogenic memory T-cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFNγ treatment inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.

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

“…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.…”

“…After finding increased Treg cells in the lungs and mLNs of IAV-immune mice, we questioned whether these expanded Treg cells participate in dysregulating normal immune responses, leading to either the increased lung pathology or viral titers that had been observed in IAV-immune mice acutely infected with LCMV (5,15). First, we determined if this increased number of Treg cells in IAV-immune mice persisted throughout the subsequent LCMV infection ( Fig.…”

Vaccination and heterologous immunity: educating the immune system

“…Notably, severe pathology can be prevented by immunizing with viral epitope mutants, by peptide tolerization against the epitope or by blockade of IFNg. 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.…”

“…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.…”

“…The mechanisms of heterologous immunity can vary, but the focus of this review is on experimental systems where both beneficial and detrimental heterologous immunity are mediated by crossreactive T cells. 22,23 More than 20 years of research have delineated basic principles of heterologous immunity, such as (1) T cell crossreactivity is quite common between unrelated pathogens and alters T cell immunodominance; 24 (2) networks of crossreactive T cells alter the efficacy of the T cell response and influence protective immunity and immunopathology; [25][26][27][28][29][30] (3) T cell crossreactivity can lead to narrowing of the T cell repertoire and generation of viral escape mutants; 31 (4) the private specificity of crossreactive T cells can determine an individual's disease outcome in regards to protective immunity and immunopathology; [31][32][33] (5) heterologous immunity can reduce the effectiveness of vaccines due to immunodominant skewing of undesired T cell responses; 29,34 (6) peptide-dependent interventions or cytokine Transactions of the Royal Society of Tropical Medicine and Hygiene blocking therapy can be used to prevent severe pathology caused by heterologous immunity; 25,30,34 and (7) the immune response to each new pathogen impacts the frequencies, distributions and activities of memory T cells to previous infections. 22,35,36 The contention is that heterologous immunity is the norm, not the exception, but given the diversity in human genetics, MHC and infection histories, is it too complicated an issue to address?…”