We previously found that memory CD4 T cells are heterogeneous in phenotype, function and homing to lymphoid and non-lymphoid tissue (1, 2).  The mechanisms for the generation of heterogeneous memory T cells and the capacity of different subsets of memory CD4 T cells to mediate protective immunity are not known, and are of direct importance for designing effective T cell-based vaccines.  We have investigated mechanisms for the generation of memory CD4 T cells by altering the extent of activation of precursor cells, which led us to develop a new model for memory generation (3, 4). In addition, we set up models for investigating how memory CD4 T cells function in anti-viral immune responses, which now constitutes a major focus of my laboratory. Little is known about the function of memory CD4 T cells in anti-viral immunity, although they can coordinate secondary responses via their direct effector functions, and their ability to “help” or promote cellular and humoral responses.  Many highly variable pathogens such as influenza virus evade antibody-based vaccines, and therefore elucidating the diverse capacities of memory CD4 T cells in anti-viral immunity is a crucial step in the development of broad-based T cell-mediated immunity. Moreover, memory CD4 T cells directed against influenza persist in the periphery and lung of older children and adults, and have the potential to mediate “first-line” immunity to viral challenge.  Understanding how protective memory CD4 T cells are formed, and how memory CD4 T cells contribute to pathogen control or immunopathology are therefore critical issues for optimizing immunity to influenza and other viral pathogens.

We have developed a novel mouse model in which immune responses to influenza virus are directed by a heterogeneous population of virus-specific memory CD4 T cells in an otherwise naive mouse host.  We found that memory CD4 T cells mediated efficient lung viral clearance, yet also promoted extensive immunopathology in the lung.  These results indicate that memory CD4 T cells exemplify the dual nature of anti-viral responses in which protection can be masked by immunopathology.  We found that the balance of protection and immunopathology to influenza challenge mediated by memory CD4 T cells can be shifted by altering IL-2 production and expansion of memory CD4 T cells by inhibiting CD28 costimulation (5, 6).  In addition, we also found that lung memory CD4 T cells have more effector function compared to lymphoid memory CD4 T cells and home to and are retained uniquely in the lung, as demonstrated by parabiosis experiments.  Importantly, lung memory CD4 T cells mediate superior protective immune responses to influenza challenge marked by rapid viral clearance, minimal morbidity, and efficient protection from lethal challenge.  Our future goals are to uncover the mechanisms by which memory CD4 T cells mediate protective responses and immunopathology and determine how best to generate lung homing memory CD4 T cells.  In addition, we will further  assess how modulation of memory CD4 T cell homing will affect protective immunity using the sphingosine receptor antagonist FTY720 that prevents lymphoid egress of T cells,.  We are also pursuing the mechanisms for the lung-tissue tropism of lung-resident memory T cells and the question of how and when lung-resident memory CD4 T cells are generated during an initial infection and effector response. These studies are funded by a newly awarded 5-year project as part of a U19 program grant with Wistar Institute, an NIH R21 grant, and a grant from Bristol-Myers Squibb.