Neuroinvasive West Nile Infection Elicits Elevated and Atypically Polarized T Cell Responses That Promote a Pathogenic Outcome

PLoS Pathogens

Vivian H. Gersuk¹  Shinobu Yamamoto¹  Eddie A. James¹  Theresa J. Gates¹  Quynh-Anh Nguyen¹  Chester Ni¹  Uma Malhotra¹  Rebecca E. LaFond¹  Brad Zeitner¹  Duy Mai¹  Kimberly O’Brien¹  Philip J. Norris²  Marion C. Lanteri²  Damien Chaussabel³  William W. Kwok⁴ 

[1] Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America;Blood Systems Research Institute, San Francisco, California, United States of America;Departments of Laboratory Medicine and Medicine, University of California, San Francisco, San Francisco, California, United States of America;Virginia Mason Medical Center, Seattle, Washington, United States of America

关键词: T cells;    West Nile virus;    Cytokines;    Regulatory T cells;    Cloning;    Cell staining;    Immune response;    Memory T cells;   

DOI  :  10.1371/journal.ppat.1005375

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Most West Nile virus (WNV) infections are asymptomatic, but some lead to neuroinvasive disease with symptoms ranging from disorientation to paralysis and death. Evidence from animal models suggests that neuroinvasive infections may arise as a consequence of impaired immune protection. However, other data suggest that neurologic symptoms may arise as a consequence of immune mediated damage. We demonstrate that elevated immune responses are present in neuroinvasive disease by directly characterizing WNV-specific T cells in subjects with laboratory documented infections using human histocompatibility leukocyte antigen (HLA) class II tetramers. Subjects with neuroinvasive infections had higher overall numbers of WNV-specific T cells than those with asymptomatic infections. Independent of this, we also observed age related increases in WNV-specific T cell responses. Further analysis revealed that WNV-specific T cell responses included a population of atypically polarized CXCR3+CCR4+CCR6- T cells, whose presence was highly correlated with neuroinvasive disease. Moreover, a higher proportion of WNV-specific T cells in these subjects co-produced interferon-γ and interleukin 4 than those from asymptomatic subjects. More globally, subjects with neuroinvasive infections had reduced numbers of CD4+FoxP3+ Tregs that were CTLA4 positive and exhibited a distinct upregulated transcript profile that was absent in subjects with asymptomatic infections. Thus, subjects with neuroinvasive WNV infections exhibited elevated, dysregulated, and atypically polarized responses, suggesting that immune mediated damage may indeed contribute to pathogenic outcomes.

【 授权许可】

CC BY