Memory T helper (Th) cells are responsible for providing multifaceted regulation of accelerated antigen-specific responses in vivo upon rechallenge with previously experienced antigens. However, the development, functional organization, and homeostasis of the long-lived memory Th cell pool remain poorly resolved. We have recently determined that four distinct subsets of memory Th cells, defined by differential expression of CD69 and a glycosylation variant of CD43, develop and persist in mice after initial priming with a defined protein antigen. Analogous subsets also comprise the CD44(hi) CD62L(low) Th cell compartment, considered to be the collective memory Th cell pool, and are conserved across different individual animals and different strains. In addition, we have determined that these novel memory Th cell subsets each display distinct calcium signaling properties in response to activation. In the current proposal, we will test the hypothesis that Th cell memory develops as multiple cellular compartments, with each specialized to provide different aspects of long-term immunity. We will first determine whether these four memory Th cell subsets possess unique functional attributes or simply represent different states of activation or turnover. Secondly, we will define whether expression of the glycosylation variant of CD43 is necessary for normal Th cell memory development and function. Collectively, these studies should establish the identity of distinct functional compartments of memory Th cells, which will ultimately lead to development of vaccine strategies and immunotherapies that exploit subsets of memory Th cell with the greatest ability to affect lasting protective immunity.
