Double-negative T resident memory cells of the lung react to influenza virus infection via CD11c(hi) dendritic cells

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Abstract

Immunity to Influenza A virus (IAV) is controlled by conventional TCR alpha beta(+) CD4(+) and CD8(+) T lymphocytes, which mediate protection or cause immunopathology. Here, we addressed the kinetics, differentiation, and antigen specificity of CD4(-) CD8(-) double-negative (DN) T cells. DNT cells expressed intermediate levels of TCR/CD3 and could be further divided in gamma delta T cells, CD1d-reactive type I NKT cells, NK1.1(+) NKT-like cells, and NK1.1(-) DNT cells. NK1.1(-) DNT cells had a separate antigen-specific repertoire in the steady-state lung, and expanded rapidly in response to IAV infection, irrespectively of the severity of infection. Up to 10% of DNT cells reacted to viral nucleoprotein. Reinfection experiments with heterosubtypic IAV revealed that viral replication was a major trigger for recruitment. Unlike conventional T cells, the NK1.1(-) DNT cells were in a preactivated state, expressing memory markers CD44, CD11a, CD103, and the cytotoxic effector molecule FasL. DNT cells resided in the lung parenchyma, protected from intravascular labeling with CD45 antibody. The recruitment and maintenance of CCR2(+) CCR5(+) CXCR3(+) NK1.1(-) DNT cells depended on CD11c(hi) dendritic cells (DCs). Functionally, DNT cells controlled the lung DC subset balance, suggesting they might act as immunoregulatory cells. In conclusion, we identify activation of resident memory NK1.1(-) DNT cells as an integral component of the mucosal immune response to IAV infection.
Original languageUndefined/Unknown
Pages (from-to)999-1014
Number of pages16
JournalMucosal Immunology
Volume9
Issue number4
DOIs
Publication statusPublished - 2016

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