Memory T cells can be divided into central memory T cell (T CM cell) and effector memory T cell (T EM cell) subsets based on homing characteristics and effector functions. Whether T EM and T CM cells represent interconnected or distinct lineages is unclear, although the present paradigm suggests that T EM and T CM cells follow a linear differentiation pathway from naive T cells to effector T cells to T EM cells to T CM cells. We show here that naive T cell precursor frequency profoundly influenced the pathway along which CD8 + memory T cells developed. At low precursor frequency, those T EM cells generated represented a stable cell lineage that failed to further differentiate into T CM cells. These findings do not adhere to the present dogma regarding memory T cell generation and provide a means for identifying factors controlling memory T cell lineage commitment.Based on homing characteristics and effector functions, at least two types of memory T cells have been described in CD4 + and CD8 + T cell populations. The original descriptions of central and effector memory T cells suggested that central memory T cells (T CM cells) reside in lymphoid organs and express CCR7 and CD62L, whereas effector memory T cells (T EM cells) reside mainly in nonlymphoid tissues, do not express CCR7 or CD62L and have immediate effector functions 1-3 . This raised the question of how T CM cells and T EM cells are generated and whether each is the product of interdependent or separate lineages.Three models of differentiation have been proposed, with the first being that T CM cells provide a continual source of T EM cells. This model is based on the findings that memory CCR7 + T cells in short-term in vitro culture can lose expression of this chemokine receptor and in the process become functionally competent1 ,4 . Analysis of the T cell receptor (TCR) repertoire of human blood memory CD8 + T cells has suggested an additional possibility in which T CM and T EM cells represent mostly separate lineages 5 . In contrast, an alternative model has indicated that over time T EM cells convert to T CM cells 6 . This conclusion was derived from analysis of TCR-transgenic CD8 + memory T cells specific for lymphocytic choriomeningitis virus (LCMV) glycoprotein 33 (gp33) that had been separated by virtue of
Type I interferons (IFN-I) are well-known inducers of tumor cell apoptosis and antiangiogenesis via signaling through a common receptor interferon alpha receptor (IFNAR). IFNAR induces the Janus activated kinase-signal transducer and activation of transcription (JAK-STAT) pathway in most cells, along with other biochemical pathways that may differentially operate, depending on the responding cell subset, and jointly control a large collection of genes. IFNs-I were found to systemically activate natural killer (NK) cell activity. Recently, mouse experiments have shown that IFNs-I directly activate other cells of the immune system, such as antigen-presenting dendritic cells (DC) and CD4 and CD8 T cells. Signaling through the IFNAR in T cells is critical for the acquisition of effector functions. Cross-talk between IFNAR and the pathways turned on by other surface lymphocyte receptors has been described. Importantly, IFNs-I also increase antigen presentation of the tumor cells to be recognized by T lymphocytes. These IFN-driven immunostimulatory pathways offer opportunities to devise combinatorial immunotherapy strategies. Clin Cancer Res; 17(9); 2619-27. Ó2011 AACR.
Type I interferons (IFN-I) are rapidly induced following infection and play a key role in nonspecific inhibition of virus replication. Here we have investigated the effects of IFN-I on the generation of antigen-specific antibody responses. The data show that IFN-I potently enhance the primary antibody response to a soluble protein, stimulating the production of all subclasses of IgG, and induce long-lived antibody production and immunological memory. In addition, endogenous production of IFN-I was shown to be essential for the adjuvant activity of CFA. Finally, IFN-I enhanced the antibody response and induced isotype switching when dendritic cells were the only cell type responding to IFN-I. The data reveal the potent adjuvant activity of IFN-I and their important role in linking innate and adaptive immunity.
CD8+ T cell responses can be generated against antigens that are not expressed directly within antigen-presenting cells (APCs), through a process known as cross-priming. To initiate cross-priming, APCs must both capture extracellular antigen and receive specific activation signals. We have investigated the nature of APC activation signals associated with virus infection that stimulate cross-priming. We show that infection with lymphocytic choriomeningitis virus induces cross-priming by a mechanism dependent on type I interferon (IFN-alpha/beta). Activation of cross-priming by IFN-alpha/beta was independent of CD4+ T cell help or interaction of CD40 and CD40 ligand, and involved direct stimulation of dendritic cells. These data identify expression of IFN-alpha/beta as a mechanism for the induction of cross-priming during virus infections.
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