Mechanisms of Lung Surveillance by Pathogen-Specific Cytotoxic T Lymphocytes

Cytotoxic T lymphocyte (CTL)-mediated immunity plays a critical role in clearance of influenza virus-infected cells through contact-dependent interactions. Recent studies have described stationary tissue-resident memory (Trm) T cells which maintain CD69 and CD103 expression in peripheral tissues after local infections. These Trm cells are believed to contribute to protection after local reinfection, because they stay near the site of inoculation. Parabiosis studies previously showed that some non-migratory virus-specific CD8 T cells expressed both CD69 and CD103 in the airways after influenza virus infection. Since the TGFβ and TcR signaling pathways induce CD103 and CD69 expression on CD8 T cells in other models, I hypothesized that environmental factors and residual viral products support sustained surveillance of the lungs by pathogen-specific CTLs. In chapter 3, I used mice that express a dominant negative form of the TGFβRII (dnTGFβRII) to investigate the role of TGFβ signals in regulation of virus-specific CTL responses in the lungs after influenza virus infection. My data showed that TGFβ signals were necessary to reduce numbers of KLRG1+ virus-specific Teff cells which were capable of making effector cytokines during early infection. In addition, TGFβ signals were required for CD103 expression on virus-specific CTLs that were retained in the lungs during the recovery stage of the infection. In chapter 4, I examined how antigen-persistence changes the virus-specific CTL response in the lungs using recombinant influenza viruses that differ in their ability to support prolonged antigen presentation. Comparisons of the CTL that responded to these viruses showed that prolonged antigen presentation reinforced expression of CD69 on virus-specific CTLs in the lung tissues, but not in the airways. I also used transfer studies to determine how CD69 influenced CD8 T cell migration in the lungs. Confocal microscopy showed that some CD69KO CTLs were collected around the blood vessels during the late stage of the infection. My data provide new insights into the generation and maintenance of virus-specific Trm cells in the lungs. CD69 and CD103 are both required for maintenance of long-lived Trm cells in the local tissues where they can provide immediate protective immunity against serologically distinct strains of influenza viruses