Transcriptional control of natural killer cell differentiation and function.

Gene expression can be modulated depending on physiological and developmental requirements. A multitude of regulatory genes, which are organized in interdependent networks, guide development and eventually generate specific phenotypes. Transcription factors (TF) are a key element in the regulatory cascade controlling cell fate and effector functions.

Monocytes control natural killer cell differentiation to effector phenotypes.

Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11b(hi)CD27(low) NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21(-/-) mice.

Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses.

It is uncertain whether NK cells modulate T cell memory differentiation. By using a genetic model that allows the selective depletion of NK cells, we show in this study that NK cells shape CD8(+) T cell fate by killing recently activated CD8(+) T cells in an NKG2D- and perforin-dependent manner. In the absence of NK cells, the differentiation of CD8(+) T cells is strongly biased toward a central memory T cell phenotype.

Superantigen-activated regulatory T cells inhibit the migration of innate immune cells and the differentiation of naive T cells.

Regulatory T cells can be used as tools to suppress pathogenic T cells in autoimmunity, graft-vs-host-disease, and transplantation. But even when high numbers of Ag-specific regulatory T cells are available, it is still possible under certain in vivo and in vitro conditions for effector T cells to escape effective control. Current reports suggest that the degree of suppression is modulated by the inflammatory milieu, which can induce resistance to suppression in effector T cells or subvert the inhibitory function of the regulatory T cells.

p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease.

The mechanisms that regulate NK cell trafficking are unclear. Phosphoinositide-3 kinases (PI3K) control cell motility and the p110gamma and p110delta isoforms are mostly expressed in leukocytes, where they transduce signals downstream of G protein coupled receptors (GPCR) or tyrosine kinase receptors, respectively. Here, we set out to determine the relative contribution of p110gamma and p110delta to NK cell migration in mice.

Dendritic cell migration to peripheral lymph nodes.

Dendritic cells are potent antigen-presenting cells endowed with the unique ability to prime T-cell responses. To present foreign antigens to na ive T cells, dendritic cells must migrate from inflamed or injured peripheral tissues to the closest draining lymph nodes through afferent lymphatic vessels. In addition, conventional dendritic cells, plasmacytoid dendritic cells and monocytes enter lymph nodes from blood crossing high endothelial venules.

CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming.

There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4(+) effector memory T (T(EM)) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4(+) T(EM) cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules.

L-selectin-negative CCR7- effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells.

T lymphocytes lacking the lymph node-homing receptors L-selectin and CCR7 do not migrate to lymph nodes in the steady state. Instead, we found here that lymph nodes draining sites of mature dendritic cells or adjuvant inoculation recruited L-selectin-negative CCR7- effector and memory CD8+ T cells. This recruitment required CXCR3 expression on T cells and occurred through high endothelial venules in concert with lumenal expression of the CXCR3 ligand CXCL9.

Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming.

Naive T cells are stimulated by antigen-presenting dendritic cells (DCs) in secondary lymphoid organs, but whether other types of cell participate in T cell priming is unclear. Here we show in mice that natural killer (NK) cells, which are normally excluded from lymph nodes, are rapidly recruited in a CCR7-independent, CXCR3-dependent manner to lymph nodes on stimulation by the injection of mature DCs. Recruitment of NK cells is also induced by some, but not all, adjuvants and correlates with the induction of T helper cell type 1 (T(H)1) responses.

Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming.

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7-/- DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation.

Apoptosis-dependent subversion of the T-lymphocyte epitope hierarchy in lymphoma cells.

Tumor cells undergoing programmed death are an attractive source of tumor-associated antigens, and evidences are available for their therapeutic efficacy in vivo when used either alone or in association with dendritic cells. However, little is known about the specificity of the immune response induced by such antigen formulation. Indeed, activation of specific proteases during apoptosis may influence the cytoplasmic degradation of proteins and the generation of CTL epitopes.