Role of Dendritic cells During Influenza Viral Infections

The Influenza virus is a major human pathogen that infects approximately 10-20% of the world’s population each year. Several influenza pandemics have occurred over the past 100 years. The most devastating of these occurred in 1918 and resulted in approximately 50 million deaths. The recent emergence of the highly virulent H5N1 bird flu has highlighted the need for more effective means of treating and preventing influenza pandemics. It has been observed that survival of influenza infections correlates with initial viral load.

Interestingly over the first few days of infection viral titers from sub-lethally and lethally infected mice are similar. The difference in survival has been linked to a severe lympopenia in influenza specific CD8+ T cells in the lethal dose of infection. It has been shown by Legge et al that this drop in numbers of CD8+ T cells is a result of fasL+ lymph node Dendritic Cells driving apoptosis of fas+ influenza specific T cells. My work in Dr. Legge’s lab is focused on identifying which lymph node DC population(s) are mediating this effect and if this apoptosis is antigen dependent. Additionally, I am interested in understanding what activation signal(s) are necessary to allow this regulatory effect.

Hornick EE, Dagvadorj J, Zacharias ZR, Miller AM, Langlois RA, Chen P, Legge KL, Bishop GA, Sutterwala FS, Cassel SL. Dendritic cell NLRC4 regulates influenza A virus-specific CD4 T cell responses through FasL expression. J Clin Invest. 2019 Apr 30;129(7):2888-2897. doi: 10.1172/JCI124937. PubMed PMID: 31038471; PubMed Central PMCID: PMC6597209.

Hemann EA, Sjaastad LE, Langlois RA, Legge KL. Plasmacytoid Dendritic Cells Require Direct Infection To Sustain the Pulmonary Influenza A Virus-Specific CD8 T Cell Response. J Virol. 2015 Dec 30;90(6):2830-7. doi: 10.1128/JVI.02546-15. PubMed PMID: 26719269; PubMed Central PMCID: PMC4810669.

Brincks EL, Gurung P, Langlois RA, Hemann EA, Legge KL, Griffith TS. The magnitude of the T cell response to a clinically significant dose of influenza virus is regulated by TRAIL. J Immunol. 2011 Nov 1;187(9):4581-8. doi:10.4049/jimmunol.1002241. Epub 2011 Sep 21. PubMed PMID: 21940678; PubMed Central PMCID: PMC3197947.

Pham NL, Pewe LL, Fleenor CJ, Langlois RA, Legge KL, Badovinac VP, Harty JT. Exploiting cross-priming to generate protective CD8 T-cell immunity rapidly. Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12198-203. doi: 10.1073/pnas.1004661107. Epub 2010 Jun 21. PubMed PMID: 20616089; PubMed Central PMCID: PMC2901444.

Langlois RA, Meyerholz DK, Coleman RA, Cook RT, Waldschmidt TJ, Legge KL. Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice. Alcohol Clin Exp Res. 2010 Aug;34(8):1425-31. doi: 10.1111/j.1530-0277.2010.01226.x. Epub 2010 May 21. PubMed PMID: 20497135; PubMed Central PMCID: PMC2910177.

Langlois RA, Legge KL. Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T cells. J Immunol. 2010 Apr 15;184(8):4440-6. doi: 10.4049/jimmunol.0902984. Epub 2010 Mar 10. PubMed PMID: 20220091; PubMed Central PMCID: PMC2851488.

Langlois RA, Legge KL. Respiratory dendritic cells: mediators of tolerance and immunity. Immunol Res. 2007;39(1-3):128-45. Review. PubMed PMID: 17917061.