tetano
Editor, Senior Moderator
J Immunol. 2016 Jun 3. pii: 1502115. [Epub ahead of print]
[h=1]Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.[/h] Erickson JJ[SUP]1[/SUP], Rogers MC[SUP]2[/SUP], Tollefson SJ[SUP]3[/SUP], Boyd KL[SUP]1[/SUP], Williams JV[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8[SUP]+[/SUP] T cell (T[SUB]CD8[/SUB]) functional impairment during acute viral LRI, but the role of T[SUB]CD8[/SUB] impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung T[SUB]CD8[/SUB] that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung T[SUB]CD8[/SUB] upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung T[SUB]CD8[/SUB] expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to T[SUB]CD8[/SUB] impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance T[SUB]CD8[/SUB] function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored T[SUB]CD8[/SUB] effector functions but increased lung pathology, indicating that LAG-3 mediates lung T[SUB]CD8[/SUB] impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung T[SUB]CD8[/SUB] functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung T[SUB]CD8[/SUB] impairment may prevent immunopathology but also contributes to recurrent lung infections.
Copyright ? 2016 by The American Association of Immunologists, Inc.
PMID: 27259857 [PubMed - as supplied by publisher]
[h=1]Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.[/h] Erickson JJ[SUP]1[/SUP], Rogers MC[SUP]2[/SUP], Tollefson SJ[SUP]3[/SUP], Boyd KL[SUP]1[/SUP], Williams JV[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8[SUP]+[/SUP] T cell (T[SUB]CD8[/SUB]) functional impairment during acute viral LRI, but the role of T[SUB]CD8[/SUB] impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung T[SUB]CD8[/SUB] that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung T[SUB]CD8[/SUB] upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung T[SUB]CD8[/SUB] expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to T[SUB]CD8[/SUB] impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance T[SUB]CD8[/SUB] function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored T[SUB]CD8[/SUB] effector functions but increased lung pathology, indicating that LAG-3 mediates lung T[SUB]CD8[/SUB] impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung T[SUB]CD8[/SUB] functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung T[SUB]CD8[/SUB] impairment may prevent immunopathology but also contributes to recurrent lung infections.
Copyright ? 2016 by The American Association of Immunologists, Inc.
PMID: 27259857 [PubMed - as supplied by publisher]