Approaches to Targeting Tissue Resident Memory T Cells in Diseases of the Lung

Tissue resident memory T cells (TRMs) play a wide variety of roles in conditions including infection and alloimmunity. In the following work, we demonstrate how TRMs can contribute both to protection and pathology, and further demonstrate TRMs can be targeted and modified to enhance or limit their contribution to diseases. We first explore their role in RSV infection, demonstrating that infants are less able to generate TRMs following RSV infection compared to adults. Furthermore, infant TRMs are Th2-skewed compared to adult TRMs, which promotes an undesirable allergy-like phenotype in the context of viral infection. With the goal of identifying the specific role of TRMs in secondary RSV infection and eliminating the contribution of other important immune cell populations in the lung, we developed a method of pulmonary TRM isolation and transfer wherein TRMs from donor mice successfully traffick to recipient airways in response to secondary RSV infection. After identifying shortcomings in the infant TRM response to RSV, we sought to identify means through which immunization could optimize TRMs toward a more desirable antiviral phenotype. First, we assessed the use of different vaccine adjuvants in maternal immunization, identifying that the use of MPLA, a Th1-skewing adjuvant, generated a more Th1 phenotype compared to the use of Alum, a Th2-skewing adjuvant. We also investigated how a biotinylated nanoparticle (bNP) vaccine product administered directly via inhalation could affect the TRM response, identifying that inhalation led to a robust TRM pool, and that formulation with bNP resulted in a more Th1-skewed TRM pool compared to antigen alone. Overall, our studies in RSV demonstrated that infants are less able to generate a robust antiviral TRM pool compared to adults in the context of RSV infection, and that TRM pools can be modulated via vaccine modifications. We also performed extensive analysis of TRMs in the context of chronic lung allograft dysfunction (CLAD) using explanted human lung samples. In CLAD compared to controls, CD8+ TRMs demonstrated a cytotoxic profile, observed both via single-cell RNA sequencing and flow cytometry. We identified enhanced expression of the NKG2D protein on cytotoxic CD8+ TRMs; a murine model of orthotopic lung transplant demonstrated that blockade of NKG2D resulted in improved physiological outcomes following lung transplantation. Overall, our work in CLAD identifies a new target to mitigate cytotoxic alloreactive CD8+ T cell responses in CLAD.