J Leukoc Biol. 2014 Feb;95(2):215-24.

Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection.

Tao Wu, Yinghong Hu, Young-Tae Lee, Keith R. Bouchard, Alexandre Benechet, Kamal Khanna, and Linda S. Cauley.

Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, USA

 

Abstract:

Previous studies have shown that respiratory virus infections leave local populations of tissue resident memory CD8 T cells (TRM cells) in the lungs, which disappear as heterosubtypic immunity declines. The location of these TRM cells and their contribution to the protective CTL response have not been clearly defined. We used fluorescence microscopy to show that some CD103+ TRM cells were embedded in the walls of the large airways long after pulmonary immunization, but were absent from systemically primed mice. Viral clearance from the lungs of the locally immunized mice preceded the development of a robust effector CD8 T cell response in the lungs. Large numbers of virus-specific CTL were found around the bronchial tree during viral clearance, but there was little involvement of the remaining lung tissue. Much larger numbers of TEM cells entered the lungs of the systemically immunized animals, but did not prevent extensive viral replication or damage to the alveoli. Together these experiments show that virus-specific antibodies and TRM cells are both required for optimal heterosubtypic immunity, while circulating memory CD8 T cells do not substantially alter the course of disease.

 

Supplement:

Cytotoxic T lymphocytes (CTLs) play an important role in immune defenses against respiratory virus infections and reduce viral titers by killing infected epithelial cells which are factories of new virus particles (Figure 1). Long lived CTLs persist after viral clearance and provide cross-protection against re-infection with other strains (1). Studies have shown that this protection lasts about six months, which corresponds with declining numbers of activated CTLs in the lungs (2). We further analyzed how virus-specific memory CD8 T cells provide immunity using mice that were infected with influenza virus via different routes of inoculation (3). In this way we were able to induce large populations of virus-specific memory CD8 T cells in the circulation, together with (or without) local populations of tissue-resident memory C8 T cells (TRM) in the airways. For imaging studies, pulmonary TRM cells were identified with antibodies to CD103, which is a TGFβ-dependent aeb7 integrin (CD103) that permits interactions with epithelial cells that express e-cadherin (4). The image in Figure 2 show CD103+ TRM cells embedded in the walls of a large airway 15 days after influenza virus infection.

All of the mice that were previously infected with influenza virus lost smaller percentages of their body weight, and recovered more rapidly after reinfection, than unprimed animals (3). We treated some animals with an immune modulator of Sphingosene-1-phosphate receptors (fingolimod or FTY720)and found that pulmonary TRM cells reduce viral titers in the lungs with very little assistance from CTLs in the circulation (3). The cross protection was partially mediated by antibodies, but the lowest viral titers were found in mice with TRM cells in the airways. One of the most important findings of our study was that the maximum numbers virus-specific CTLs in the lungs were greatly reduced when TRM cells were present before reinfection.

Overall we showed that pulmonary TRM cells do not work in isolation, but contribute to multiple layers of protection in the lungs which collaborate to accelerate viral clearance. Recent reports in the literature suggest that TRM cells in other tissues alert the immune system of impending danger by increasing local inflammatory responses, which recruit large numbers of immune cells to site of infection (5). In contrast, the pulmonary TRM cells in our studies appeared to have anti-inflammatory properties which prevented excessive infiltration of immune cells around the alveoli. Massive infiltrations of virus-specific CTLs were found in the lung parenchyma when circulating memory CD8 T cells were not accompanied by TRM cells. Whether pulmonary TRM cells play a direct role in viral clearance is not known, but lytic activity may play a critical role in protection.

Acknowledgements: This work was supported by U.S. National Institutes of Health grants AI056172 and AI071213.

Contacts:

Linda S. Cauley Ph.D.

UCONN Health, Department of Immunology,

263 Farmington Ave., Farmington,

CT 06032-1319, USA.

E-mail: lcauley@uchc. Edu

 

References:

1.    Liang, S., K. Mozdzanowska, G. Palladino, and W. Gerhard. 1994. Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. J. Immunol. 152: 1653-1661.

2.    Hogan, R. J., E. J. Usherwood, W. Zhong, A. A. Roberts, R. W. Dutton, A. G. Harmsen, and D. L. Woodland. 2001. Activated antigen-specific CD8+ T cells persist in the lungs following recovery from respiratory virus infections. J. Immunol. 166: 1813-1822.

3.    Wu, T., Y. Hu, Y. T. Lee, K. R. Bouchard, A. Benechet, K. Khanna, and L. S. Cauley. 2013. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95: 225-232.

4.    Cepek, K. L., S. K. Shaw, C. M. Parker, G. J. Russell, J. S. Morrow, D. L. Rimm, and M. B. Brenner. 1994. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372: 190-193.

5.    Schenkel, J. M., K. A. Fraser, V. Vezys, and D. Masopust. 2013. Sensing and alarm function of resident memory CD8 T cells. Nat. Immunol.

Figure-13

Figure 1. Influenza viruses replicate inside lung epithelial cells and spread throughout the bronchial tree. Irreparable damage can occur when the virus reaches the alveoli. Peak viral titers are reduced by cytotoxic T lymphocytes which kill infected cells before additional virus is released.  The immune response develops rapidly when TRM cells are waiting in the airways and mild inflammation protect the lungs from severe damage.
Figure-22

Figure 2. Images of TRM cells in the lungs after influenza virus infection. Naïve CD8 T cells that are specific for an epitope in the influenza virus nucleoprotein gene were transferred to mice two days before infection and the lungs were analyzed 15 days later. A) Virus-specific CTLs (green) are embedded in the wall of the airway (red), which located next to a large  blood vessel (yellow. B) TRM cells were identified using CD103 expression (magenta). The image was taken at normal magnification X40.

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