Publications by Year: 2002

2002
Román E, Miller E, Harmsen A, Wiley J, von Andrian UH, Huston G, Swain SL. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function. J Exp Med. 2002;196 (7) :957-68.Abstract
The immune response of naive CD4 T cells to influenza virus is initiated in the draining lymph nodes and spleen, and only after effectors are generated do antigen-specific cells migrate to the lung which is the site of infection. The effector cells generated in secondary organs appear as multiple subsets which are a heterogeneous continuum of cells in terms of number of cell divisions, phenotype and function. The effector cells that migrate to the lung constitute the more differentiated of the total responding population, characterized by many cell divisions, loss of CD62L, down-regulation of CCR7, stable expression of CD44 and CD49d, and transient expression of CCR5 and CD25. These cells also secrete high levels of interferon gamma and reduced levels of interleukin 2 relative to those in the secondary lymphoid organs. The response declines rapidly in parallel with viral clearance, but a spectrum of resting cell subsets reflecting the pattern at the peak of response is retained, suggesting that heterogeneous effector populations may give rise to corresponding memory populations. These results reveal a complex response, not an all-or-none one, which results in multiple effector phenotypes and implies that effector cells and the memory cells derived from them can display a broad spectrum of functional potentials.
von Andrian UH. Immunology. T cell activation in six dimensions. Science. 2002;296 (5574) :1815-7.
Lange-Asschenfeldt B, Weninger W, Velasco P, Kyriakides TR, von Andrian UH, Bornstein P, Detmar M. Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2--deficient mice. Blood. 2002;99 (2) :538-45.Abstract
Angiogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2-deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2-deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found in the inflamed skin of TSP-2-deficient mice. Moreover, the fraction of rolling leukocytes was significantly increased in the untreated skin of TSP-2-deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell infiltration during acute and chronic inflammation.
Weninger W, Manjunath N, von Andrian UH. Migration and differentiation of CD8+ T cells. Immunol Rev. 2002;186 :221-33.Abstract
Antigen-specific responses by CD8+ T cells require direct cell-cell interactions between T cells and antigen-presenting cells (APC). Initially, naïve T cells must communicate with APC in lymphoid organs. Once stimulated, the resulting effector cells interact with APC in peripheral tissues. To this end, T cells must migrate to discrete sites throughout the body where antigen may be found. Recent progress in the field has revealed that the migratory abilities of T cells are critically dependent on their differentiation state, which is shaped by a multitude of factors. Thus, naïve T cells are normally restricted to recirculate between the blood and secondary lymphoid tissues, although in some autoimmune diseases they may also accumulate in chronically inflamed tissues. When CD8+ T cells encounter antigen and differentiate into short-lived effector CTL, they lose the ability to home to lymph nodes but gain access to peripheral tissues and sites of inflammation. Long-lived memory cells exist in (at least) two flavors: central memory cells that migrate to both lymphoid organs and peripheral sites of inflammation, and effector memory cells that are preferentially localized in non-lymphoid tissues. Our current understanding of the interplay of T cell differentiation and migration has been boosted by the development of T-GFP mice, in which transgenic green fluorescent protein is expressed selectively in naïve and central memory T cells, but not in effector cytotoxic T cells (CTL). This review will focus on recent studies in which T-GFP mice were used to dissect the traffic signals for naïve T cell homing to secondary lymphoid organs, the factors that influence the differentiation of naïve CD8+ T cells into cytotoxic and memory cells, as well as the in vivo trafficking routes of antigen-experienced subsets.
Mazo IB, Quackenbush EJ, Lowe JB, von Andrian UH. Total body irradiation causes profound changes in endothelial traffic molecules for hematopoietic progenitor cell recruitment to bone marrow. Blood. 2002;99 (11) :4182-91.Abstract
Nonirradiated bone marrow (BM) venules and sinusoids in murine skull support hematopoietic progenitor cell (HPC) rolling through constitutively expressed endothelial (P- and E-) selectins and VCAM-1. Using intravital microscopy, we tested whether host conditioning with total body irradiation (TBI) changes the molecular mechanisms by which murine HPCs from fetal livers (FL) interact with BM endothelial cells. Although a high dose of TBI did not affect the overall frequency of HPC rolling in BM microvessels, the underlying molecular mechanisms differed from those in nonirradiated BM. TBI induced VCAM-1 up-regulation in BM microvessels, whereas P-selectin expression was reduced and the low baseline level of E-selectin remained unchanged. Only the administration of anti-VCAM-1, but not anti-P- or -E-selectin monoclonal antibodies, decreased FL HPC rolling. Rolling was frequently followed by firm arrest (sticking), even in nonirradiated BM microvessels in which sticking was entirely pertussis toxin-insensitive-that is, Galpha(i)-coupled signaling events (eg, through chemokines) were apparently not required. TBI increased the frequency of sticking FL HPC. This irradiation-induced additional sticking was reversed when FL HPCs were pretreated with pertussis toxin, suggesting that TBI induced elevated expression of a Galpha(i)-protein-coupled chemotactic signal in the BM. This chemoattractant was probably distinct from SDF-1alpha because, unlike adult HPCs, FL HPCs (day 11 of gestation) responded poorly to SDF-1alpha in vitro. These results demonstrate that TBI induces profound changes in the expression of endothelial traffic molecules in the BM, and they indicate that FL HPCs can home to the BM in the absence of SDF-1alpha and other Galpha(i)-protein-coupled signals.
Cavanagh LL, von Andrian UH. Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol. 2002;80 (5) :448-62.Abstract
The migratory behaviour of dendritic cells (DC) is tightly linked to their differentiation state. Precursor DC constitutively repopulate normal tissues from the bloodstream, and are recruited in elevated numbers to sites of inflammation. Whilst maturing in response to antigenic stimulation, DC acquire the capability to enter lymph nodes via afferent lymphatic vessels, thus facilitating their presentation of antigen to naïve T cells. Peripheral blood monocytes constitute a second DC precursor population, which during an inflammatory response are recruited to the affected site where some differentiate into functional DC. The availability of separate DC precursor populations is thought to be significant for the character, amplification and perpetuation of the resultant immune response. In addition, the balance between steady-state trafficking of incompletely activated DC bearing self-antigens from the periphery, and the migration of fully mature DC from inflammatory sites into lymph nodes might have profound effects upon tolerance induction and activation of T cells, respectively.