Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.

Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-γ and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-γ and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-β. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

T cells are imprinted to express tissue-specific homing receptors upon activation in tissue-draining lymph nodes, resulting in their migration to the site of Ag entry. Expression of gut-homing molecules α4β7 and CCR9 is induced by retinoic acid, a vitamin A metabolite produced by retinal dehydrogenases, which are specifically expressed in dendritic cells as well as stromal cells in mucosa-draining lymph nodes. In this study, we demonstrate that mesenteric lymph node stromal cell-derived retinoic acid can directly induce the expression of gut-homing molecules on proliferating T cells, a process strongly enhanced by bone marrow-derived dendritic cells in vitro. Therefore, cooperation of sessile lymph node stromal cells with mobile dendritic cells warrants the imprinting of tissue specific homing receptors on activated T cells.

Tissue-specific homing of effector and memory T cells to skin and small intestine requires the imprinting of specific combinations of adhesion molecules and chemokine receptors by dendritic cells in the draining lymph nodes. In this study, we demonstrate that CD8 U pon activation by dendritic cells (DC)3 in skin-draining lymph nodes, T cells up-regulate the skin-homing receptors E-(E-lig) and P-selectin ligands as well as the chemokine receptors CCR4 and CCR10 (1-6). Activation by DC from mesenteric lymph nodes (MLN) and Peyer's patches (PP) induces the small intestine homing receptors ␣ 4 ␤ 7 integrin and CCR9 (4 -9). The role of lymph node-resident DC vs DC that immigrated from peripheral tissues has not yet been addressed. DC from MLN and PP express retinal dehydrogenases (RALDH). They produce the vitamin A metabolite retinoic acid (RA) that induces up-regulation of ␣ 4 ␤ 7 and CCR9 (10). Lamina propria-derived CD103 ϩ DC are responsible for the imprinting of gut homing receptors on T cells in PP and MLN (11,12). Epidermal Langerhans cells were most efficient in the induction of skin-homing receptors on CD8 ϩ T cells in vitro as compared with DC from skin-draining lymph nodes (4, 6). These findings suggest that the DC immigrating into draining lymph nodes from peripheral tissues, rather than the lymph node resident DC, are responsible for homing receptor imprinting. In support of this view, two independent homing phenotypes can be induced on T cells in the same lymph node by DC that immigrated from different peripheral sites (13). Moreover, the majority of DC in skin draining lymph nodes consists of immigrants, i.e., Langerhans cells and dermal DC (14).For this work, we have studied the role of the peripheral tissue microenvironment in the imprinting of skin and small intestine homing receptors by DC in coculture systems. CD8 ϩ P14 T cells (15,16), upon activation with Ag-pulsed bone marrowderived DC (BM-DC), up-regulated the skin-homing receptor E-lig in coculture with dermal fibroblasts or the gut homing receptors CCR9 and ␣ 4 ␤ 7 in coculture with small intestinal epithelial cells (SIEC). Soluble factors such as RA induced the imprinting of the gut homing phenotype, whereas cell-cell contact with dermal fibroblasts was important for the induction of E-lig on T cells. Our findings suggest that peripheral tissue stromal and epithelial cells produce factors that can directly induce homing receptors on T cells. These factors may license DC to also produce such factors and/or allow for the DC to shuttle these imprinting factors to the naive T cells in the regional draining lymph nodes. Materials and Methods MiceC57BL/6 and TCR-transgenic Thy1.1 congenic P14 mice (15, 16) were provided by the breeding facility