Date Published: March 4, 2016
Publisher: Public Library of Science
Author(s): Jie Liu, Elias K. Haddad, Joshua Marceau, Kaitlyn M. Morabito, Srinivas S. Rao, Ali Filali-Mouhim, Rafick-Pierre Sekaly, Barney S. Graham, Paul G. Thomas.
CD8 T cells are involved in pathogen clearance and infection-induced pathology in respiratory syncytial virus (RSV) infection. Studying bulk responses masks the contribution of individual CD8 T cell subsets to protective immunity and immunopathology. In particular, the roles of subdominant responses that are potentially beneficial to the host are rarely appreciated when the focus is on magnitude instead of quality of response. Here, by evaluating CD8 T cell responses in CB6F1 hybrid mice, in which multiple epitopes are recognized, we found that a numerically subdominant CD8 T cell response against DbM187 epitope of the virus matrix protein expressed high avidity TCR and enhanced signaling pathways associated with CD8 T cell effector functions. Each DbM187 T effector cell lysed more infected targets on a per cell basis than the numerically dominant KdM282 T cells, and controlled virus replication more efficiently with less pulmonary inflammation and illness than the previously well-characterized KdM282 T cell response. Our data suggest that the clinical outcome of viral infections is determined by the integrated functional properties of a variety of responding CD8 T cells, and that the highest magnitude response may not necessarily be the best in terms of benefit to the host. Understanding how to induce highly efficient and functional T cells would inform strategies for designing vaccines intended to provide T cell-mediated immunity.
Respiratory syncytial virus (RSV) induces robust CD8 T cell responses that play a critical role in controlling virus replication and determining the progression of disease in animal models and infected humans. For example, autopsies of children with fatal RSV infections show a relative deficiency of CD8 T cell responses; recipients of allogeneic bone marrow and lung transplants have difficulty in controlling RSV replication and often have fatal outcomes as a consequence of syncytium-forming pneumonia[2, 3]; and in patients with severe combined immunodeficiency (SCID), RSV infection results in persistent virus shedding that can be controlled with T cell reconstitution[4, 5]. Adoptive transfer of effector CD8 T cells can clear persistent RSV shedding in immunodeficient mice; and depletion of T cells in mice results in persistence of the virus[7, 8]. However, the effect of CD8 T cell responses is not always beneficial. While T cell reconstitution reduces RSV load in SCID patients, it causes significant pulmonary inflammation. In mice, passive transfer of a large amount of CD8 T cells in the setting of RSV infection results in hemorrhagic pneumonia, while depletion of CD8 T cells reduces disease severity. Achieving an acceptable balance between protective immunity and immunopathology has been an elusive goal for RSV vaccine development and is a key objective for programs developing preventive and therapeutic strategies for pathogens requiring T cell-mediated immunity.
It has become increasingly evident that magnitude of CD8 T cell response does not necessarily correlate with the extent of protection from infectious pathogens, and that functional properties of T cells may be more predictive of infection outcome[11, 12, 42]. In addition, the analysis of polyclonal T cell responses in bulk masks the functional diversity of T cells responding to specific epitopes. Even within an epitope-specific response, there are clonotype-specific subsets, each with their own functional profiles that collectively determine the characteristics of the overall response[9, 10]. Defining the characteristics of CD8 T cells that can efficiently clear virus-infected cells with minimal immunopathology has obvious implications for developing interventions that provide T cell-mediated immunity.