John Teijaro, PhD

My focus is on studying persistent viral infection using the LCMV system and acute viral pathogenesis utilizing the influenza virus in a mouse model. I have been trained in the growing and titrating LCMV as well as infecting mice with various LCMV clones. I have experience quantifying and analyzing functionality of virus specific T cells. I am currently investigating the role type 1 interferon plays in the initiation and maintenance of persistent virus infection and how type 1 interferon signaling promotes cytokine amplification and immune pathology during influenza virus infection. I have experience working at the interface of virology and immunology. During my graduate studies I set up an influenza virus infection system to investigate memory CD4 T cells responses to influenza virus infection in mice with Donna Farber. With Donna I identified that memory CD4 T cells contribute to both protection and immune pathology following influenza virus challenge. We demonstrated that memory CD4 T cells could provide protection independently of CD8 T cells or B cells by a mechanism requiring IFN-?. Moreover, we were the first lab to demonstrate the existence of tissue resident memory CD4 T cells in the lung and that these resident memory T cells provided optimal protection to influenza virus re-challenge. I continued my training in viral immunology by gaining expertise in both the LCMV and Influenza virus systems with Michael Oldstone. During my time in Michael’s laboratory, I shifted my focus in two directions, 1) towards innate immune responses and understanding how innate cytokine amplification during influenza virus infection contributes to disease pathogenesis and 2) studying how the immune system controls persistent LCMV (clone-13) infection. My work on cytokine amplification during influenza virus infection resulted in the surprising finding that endothelial (not epithelial) cells were central regulators of cytokine amplification during influenza virus. Moreover, blunting this cytokine amplification during human pathogenic influenza virus infection resulted in improved survival, demonstrating for the first time that innate immune pathology is causal in influenza virus pathogenesis. The future directions focus on understanding the pulmonary cellular players that initiate and amplify cytokines/chemokines following influenza virus challenge. Further, we recently demonstrated that blockade of type 1 interferon signaling during persistent LCMV infection resulted in hastened clearance of persistent LCMV from mouse hosts. We demonstrate that blockade of type 1 interferon (IFN-I) signaling using a type 1 interferon receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus (LCMV). IFN-I blockade both prior to and following establishment of persistent virus infection resulted in a CD4-T cell dependent enhanced virus clearance. We demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization and virus persistence.

My lab is now leveraging our work on immune suppressive environments during persistent virus infection to understand cancer immune suppression with the goal of identifying novel treatments and modalities to promote T cell eradication of tumors. Towards this end, we recently identified that JAK inhibition with small molecule antagonists can enhance tumor control in both mouse models and human cancer in conjunction with checkpoint therapy. This new study in the lab began with our previous observation that type 1 interferons promote immune suppressive environments in persistent LCMV infection in mice, a result that has been subsequently confirmed in mouse cancer models (Andy Minn Laboratory, Cell 2016) as well as in human cancer patients (David Brooks Laboratory, Nat. Immunol. 2022) responding to checkpoint therapy. In a recent paper from our laboratory, we reported that JAK inhibition could revive checkpoint immunotherapy responses in relapsed/resistant patients with classic Hodgkin Lymphoma in a phase 1 trial. We are very excited to test whether JAK inhibition in combination with checkpoint immunotherapy can enhance response to solid tumors in mice. Further, studying samples from cancer patients treated with checkpoint therapy, we will assess the ability of JAK inhibition to modulate myeloid and lymphoid cell responses to set the stage for an IIT assessing JAK inhibition in combination with checkpoint blockade in immunotherapy refractory/resistant patients.  

More recently, my laboratory has been moving towards employing my expertise in small molecule modulation of immune responses with my background in viral immunology and immune suppressive environments to transition to investigating human immune responses and whether basic concepts in the mouse can be used to instruct immunomodulation of human immune responses. Our work will extend our analysis of how chronic viral infection and cancer immune environments regulate T cell-APC interactions and the outcomes of the immune responses in both untreated and checkpoint treated animals.