An important distinguishing feature of the adaptive immune response is the de-velopment of immunologic memory, which provides protective immunity against repeat pathogen encounters. T lymphocytes, including the CD4 and CD8 T cell subsets, are both known to persist as memory. Despite increasing knowledge of the mechanisms un-derlying T cell activation and function, the generation, maintenance and protective effi-cacy of T cell memory remains poorly defined. At present, there are no existing vaccine strategies to generate memory T cell mediated protective immunity. Furthermore, the qualities that define a protective memory T cell response are incompletely understood. Our laboratory has identified heterogeneous populations of influenza hemaggluti-nin (HA) specific memory CD4 T cells, with respect to phenotype, function, and migra-tion to both secondary lymphoid and peripheral tissues. However, how these diverse memory CD4 T cell subsets mediate protection to influenza virus infection remains un-explored. In order to investigate protection mediated my memory CD4 T cells, we established complementary models using TCR-transgenic and polyclonal influenza-specific T cells. Herein we deomonstrate that the presence of memory CD4 T cells in BALB/c mice resulted in enhanced viral clearance in the context of slightly increased morbidity as measured by weight loss and physical appearance. In addition, reduction in viral loads by memory CD4 T cells was not affected in the absence of B cells or CD8 T cells, and ap-peared to be IFN-γ dependent. In addition, we demonstrate that lung-derived memory preferentially migrate to and are retained within the lung tissue and facilitate rapid clear-ance of virus compared to spleen-derived memory CD4 T cells, which provided no bene-ficial protection compared to naive controls. Moreover, viral clearance in mice receiving lung memory CD4 T cells occurred in the context of reduced weight loss and physical morbidity. Finally, we demonstrate that the physiological outcome of a memory CD4 T cell-mediated secondary response to influenza can be significantly improved by targeting the CD28 pathway with the costimulation modulator CTLA4Ig. While CTLA4Ig is sup-pressive for primary immune responses to influenza, leading to increased viral loads, re-duced lung function and increased morbidity. In contrast, CTLA4Ig treatment of mem-ory CD4 T cell-mediated secondary responses to influenza is remarkably curative, result-ing in less morbidity and immunopathology, improved lung function, and enhanced re-covery. The optimized secondary response induced by CTLA4Ig treatment is character-ized by reduced lymphoid memory responses and recruitment to the lung, with intact in situ lung memory T cell responses and effector function. Our results reveal the dual na-ture of memory T-cell-mediated secondary responses and identify protective subsets, and suggest costimulation modulation as a novel strategy to optimize anti-viral immunity by limiting the memory T-cell response to its protective capacities.