Immunological memory refers to the dramatic and effective response to previously encountered antigens (Ag) that is largely regulated by T cells. Upon challenge, memory T cells localize in sites of Ag exposure and develop in effector cells that produce cytokines and chemokines that regulate the memory response. Identifying parameters that control memory T cell entry into tissue is crucial for understanding regulation of memory and alterations in T cell migration during disease processes that will be essential for strategies to potential memory in the design of vaccines and to dampen memory in allergic and autoimmune responses. Lymphocyte entry into tissue from blood is orchestrated by multiple adhesion receptors whose expression is modulated by cytokines and whose avidity is regulated by chemokines which exert selective chemoattractant effects on subsets of cells. However, mechanisms that initiate and regulate recruitment of memory T cells to sites of antigen exposure have not yet been identified. We proposed that memory T cells become activated by Ag presented by APC in tissues through which they recirculate, and then acquire the capacity to enter other sites of Ag exposure. Upon reencounter with Ag, activated memory CD4 cells produce mediators which regulate cellular recruitment. The proposed studies will investigate 4 key parameters in regulation of memory T cell migration: Ag, adhesion molecules, cytokines, and chemokines. We will use a defined adoptive transfer model to study Ag-induced recruitment of memory CD4 cells into lymphoid tissues but will also extend our studies to CD8 memory cells, in collaboration with Project 2, since there may be fundamental differences in their regulation. We will use TCR transgenic mice to generate defined memory populations and analyze the kinetics of their activation, division, and death with different conditions of immunization and determine if the recruitment response depends upon inflammation. To define contributions of adhesion receptors, cytokines, and chemokines, we will use blocking reagents at various times with respect to immunization to distinguish roles in the initiation versus progression of the response. We will also take advantage of cytokine and adhesion molecule knock out mice. In collaboration with Project 1 and 2, we have the potential to link these factors that may also affect the induction, expansion, and survival of memory cells with their subsequent ability to respond to Ag upon challenge. By using different CD4 and CD8 transgenics as sources of memory cells which can be identified by Class II and Class I tetramers, respectively, we can test predictions about normal memory responses of heterogeneous populations. These studies address fundamental questions regarding the mechanisms by which memory T cells mediate immune surveillance and provide long lasting immunity.
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