Respiratory virus infections, such as those caused by influenza and parainfluenza viruses, pose substantial immunological demands on the mucosal surface of the lungs. However, we have only a rudimentary understanding of how cellular immune responses control and eradicate pulmonary infections. Recently, using Sendai virus as a mouse model of parainfluenza virus infection, we have identified a population of highly activated memory CD4+ T cells that persists in the lungs for months following recovery from an infection or following vaccination. Furthermore, we have shown that memory CD4+T cells mediate accelerated clearance of a secondary virus infection in the absence of antibody and that at least part of this control can be attributed to memory CD4+T cells that persist in the lung. These studies demonstrate that CD4+T cells can play an important role cellular immunity in the lung, but raise a substantial number of questions regarding their mechanism of action. In the current application, we propose to determine the precise contribution of memory CD4+T cells to secondary cellular immune responses and the capacity of different vaccine strategies to promote CD4+T cell immunity.
In Aim 1, we will determine how memory CD4+ T cells are maintained in the lung and how they participate in cellular immune responses to secondary infection. In particular, intratracheal transfer of marked lung memory T cells into naive mice will allow us to directly assess the proliferation and expression of effector functions by lung memory CD4+T cells during a secondary infection. This approach will also determine whether lung memory CD4+T cells accelerate the recruitment of host T cells and cells of the innate immune system.
In Aim 2, we will determine the mechanisms through which CD4+T cells mediate enhanced viral clearance. Studies will focus on whether CD4+T cells act alone, or whether there are requirements for other cell types. In addition, we will determine the roles of cytokines and CD4+T cell cytotoxicity in mediating enhanced viral clearance.
In Aim 3, we will determine optimal vaccination strategies for eliciting CD4+T cell immunity. Thus, we will assess the capacity of DNA vaccination, intranasal vaccination, and dendritic cell vaccination to induce anatomically and phenotypically distinct populations of memory CD4+T cells and compare this with the capacity to mediate accelerated viral clearance. Taken together, these studies will determine the mechanisms underlying CD4+T cell immunity to respiratory virus infections and the parameters that are critical for the development of vaccines designed to emphasize cellular immunity in the lung.
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