Immunologic memory, the induction of a more rapid and dramatically effective immune response following re-exposure to antigen (Ag), is a fundamental but poorly understood process mediated in part by helper (CD4+) T lymphocytes (Th). Elucidating the parameters that regulate memory Th and establishing methodology for manipulating memory Th is of crucial importance for the development of effective vaccines, and as well as for targeted immunotherapy. While many studies have examined specific activation of Th lines or polyclonal activation of mixed Th populations from normal animals in vitro, proposed here is a detailed study of the development, recirculation, and function of normal memory Th using Ag-specific responses. I will employ both in vitro and in vivo models which have enabled distinction of 4 stages of Th development: naive precursors, primary effectors, resting memory cells, and recently activated memory cells (memory effectors). I will examine the role of lymphokines/cytokines and different Ag-presenting cell (APC) populations in the induction of memory Th. I will use exogenous lymphokines, soluble lymphokine receptors, or antibodies that block their function to manipulate the development of Th subsets, and will investigate controlled/sustained delivery (e.g. diffusion chambers and time release pellets) of lymphokines to enhance/promote memory Th subset development. I will also examine the recirculation pathways and activation requirements of memory and naive Th. Memory Th will be isolated using phenotypic markers which exhibit altered expression following Ag-activation (e.g. Pgp-1, CD45RB, and MEL-14), and will be evaluated using as functional criteria, Ag- induced lymphokine production, helper activity (B cell isotype production), and proliferation, as well as the capacity to transfer long-term Ag-specific Th function to adoptive recipients. The use of T cell receptor transgenic mice which express a single alpha/beta receptor specific for a defined peptide of cytochrome C will enable direct comparison of the activation/APC requirements of naive and memory Th. These studies will provide basic information on the regulation of Th development and recirculation, and conditions for selective induction/differentiation of memory Th subsets, identified by secretion of different arrays of lymphokines. The results may suggest approaches for expansion/selection of Ag-specific memory Th. If the regulation of memory were better understood, it might be possible to promote its development to enhance the effectiveness of vaccines and to exploit the properties of memory Th (enhanced responsiveness and capacity to migrate to sites of Ag concentration) to enable targeted delivery of lymphokines for the immunotherapeutic resolution of diseases and/or tumors.
