"Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype." 

Erickson et al., J. Immunol. 2015 Sep 23. pii: 1403004.

• CD8+ T cells (TCD8) possess critical functions that protect against intracellular pathogens and cancer. 
• During an acute infection, naive TCD8 cells encounter antigen, become activated and proliferate to clear the infection, after which 90–95% die. The remaining ~5%  become memory cells.
• However during a chronic infection, this sequence of events changes.

  Pathogen-specific TCD8 cells initially acquire effector functions, but they gradually become exhausted and fail to eliminate the infection.

• Interestingly, the paradigm of TCD8 exhaustion does not hold for all infection. When it comes to lower respiratory tract viral infections, murine infection models indicate that pulmonary TCD8 cells become functionally impaired, rapidly losing cytotoxicity and cytokine production. However, in contrast to exhaustion, impairment of the lung TCD8 cells during lower respiratory tract infection occurs rapidly. Additionally, only TCD8 cells in the respiratory tract become impaired; TCD8 in lymphoid organs maintain their effector functions, suggesting that the infected lung environment is critical for the development of impairment.
• This rapid impairment of effector T cells may be the basis of poor memory generation, thereby explaining why respiratory viruses and other pathogens can re-infect individuals over and over. Thus, a better understanding of this process will elucidate better ways to understand and combat chronic infections.
• Erickson et al. sought to identify mechanisms that contribute to TCD8 cell impairment in the lung, using a Human MetaPneumoVirus (HMPV) murine infection model. 
• The authors performed global transcriptional analyses, comparing the genetic programs of impaired virus-specific lung TCD8 cells to unimpaired spleen TCD8 cells in the same HMPV-infected mice.  
• Their analyses demonstrated that the lung TCD8 gene expression signature was similar to TCD8 early in the exhaustion process; however, when focusing solely on genes with known immune functions, impaired lung TCD8 were most similar to fully exhausted cells.
• Erickson et al. then confirmed that impaired lung TCD8 cells coexpress  inhibitory receptors to a greater degree than do spleen TCD8 cells. TCD8 inhibitory receptor expression was subsequently shown to be driven by antigen-dependent T cell receptor (TCR) signaling. The authors demonstrated that without TCR stimulation, TCD8 cells remain functional with very low inhibitory receptor expression.
• Collectively, the findings of Erickson et al indicate that acute viral lower respiratory infection induces an exhaustion-like state in lung TCD8 cells characterized by rapid functional impairment and Antigen-dependent upregulation of numerous inhibitory receptors.