S5). recovery from lymphopenia. Diaveridine Keywords:homeostasis, host defense, lymphopenia, CD4 T cells The establishment of a sustained, functional CD8+memory T cell pool is critical for protective immunity against many pathogens and tumors (1). Typically, memory T cells are generated after priming by a foreign antigen, with the memory population appearing as the effector pool declines. However, in response to T cell lymphopenia, nave T cells slowly proliferate Fos Diaveridine and transition to a memory-like state in a process termed homeostatic proliferation (HP) (2). Unlike conventional memory T cells, which are induced in response to foreign peptideMHC complexes and inflammatory cues, HP-memory T cells are produced in response to homeostatic cytokines (IL-7, IL-15) and engagement with self-peptideMHC complexes (1,2). Furthermore, the conversion from nave to HP-memory cells does not appear to pass through an effector cell stage or the expansion and contraction phases typical of conventional immune responses. Nonetheless, these HP-memory T cells display phenotypic Diaveridine and functional characteristics of antigen-experienced memory cells (2), including the ability to control lethal bacterial infection (3). HP-memory T cells arise during lymphopenia induced by irradiation or genetic T cell deficiency, making this process relevant for therapeutic strategies designed to reconstitute the immune system, such as after cancer therapy. Indeed, lymphopenia can augment the antitumor response following adoptive T cell immunotherapy approaches (46). In addition, lymphopenia occurs during infection with various pathogens (7,8), and Diaveridine some (for example, HIV) induce sustained T cell depletion. Finally, lymphopenia occurs in physiological situations: during ontogeny of the immune system, T cell numbers are low and there is evidence that very young mice support the production of HP-memory cells derived from nave precursors (911). Hence, HP-memory T cells may be produced in response to various lymphopenic episodes and could contribute to future immune responses. Therefore, it is important to determine the functional characteristics of this pool and their therapeutic potential. Much is known about the requirements for efficient generation of conventional memory CD8+T cells. Nave T cells require stimulation through the T cell receptor (TCR) by Diaveridine foreign peptideMHC ligands, engagement of costimulatory molecules, and cytokines (such as IL-12 or type I IFN) that enhance the T cell response (12). Adjuvants, such as Toll-like receptor (TLR) agonists, are important for enhancing antigen presentation and production of cytokines, such as IL-12. Furthermore, it has become clear that CD4+T cells play a key role in generating effective memory CD8+T cells in response to cellular and microbial antigens. The requirements for the production of effective HP-memory CD8+T cells are much less well defined. We recently demonstrated a role for CD4+T cells in the generation of protective HP-memory CD8+T cells (3). We observed that proliferation of nave CD8+T cells in lymphopenic hosts occurs regardless of the presence of CD4+T cells, but that the protective capacity of the resultant HP-memory CD8+T cells was dramatically impaired when they were generated in the absence of CD4+T cells (3). This finding may be especially relevant to situations of sustained lymphopenia and CD4 depletion (e.g., in HIV/AIDS), where the protective function of CD8+T cells may be compromised. However, the mechanism by which CD4+T cells offer help to CD8+T cells during HP is not understood. In this study we address the basis by which both CD4+T cells and factors induced by lymphodepletion dictate the protective function of HP-memory CD8+T cells. Our data suggest unexpected parallels in the requirements for regulating function of both HP- and conventional-memory.