Biomedical subjects

Kevin L Legge

Publications and source records attributed to Kevin L Legge.

4 recordsLinked to original sources

PubMed2006

T cell conditioning explains early disappearance of the memory CD8 T cell response to infection.

Memory CD8 T cells respond more rapidly to acute intracellular infections than naive CD8 T cells. An understanding of the biological processes involved in memory CD8 T cell recognition of Ag and up-regulation of effector mechanism necessitates analyzing memory CD8 T cells at early time points after infection. In the current study, we show that memory CD8 T cells ostensibly disappear from the spleens, blood, and peripheral organs of mice early after infection with Listeria monocytogenes. This disappearance is critically dependent on Ag, and cell-associated Ag alone can mediate this phenomenon. Further investigations, however, suggest that this disappearance is secondary to T cell-APC interactions, also known as T cell conditioning, and disruption of these putative interactions during splenic processing improves recovery of Ag-specific memory CD8 T cell populations after immunization. Conventional analyses of memory CD8 T cell populations early after infection and possibly in the presence of low levels of Ag (as during chronic infections) may exclude significant numbers of the responding CD8 T cell population.

Animals↗

PubMed2005

Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression.

The lethal outcome of high-dose pulmonary virus infection is thought to reflect high-level, sustained virus replication and associated lung inflammation prior to development of an adaptive immune response. Herein, we demonstrate that the outcome of lethal/sublethal influenza infection instead correlates with the initial virus replication tempo. Furthermore, the magnitude of early lung antiviral CD8+ T cell responses varies inversely with inoculum dose and is controlled by lymph-node-resident dendritic cells (LNDC) through IL-12p40-regulated FasL-dependent T cell apoptosis. These results suggest that the inoculum dose and replication rate of a pathogen entering the respiratory tract may regulate the strength of the adaptive immune response, and the subsequent outcome of infection and that LNDC may serve as regulators (gatekeepers) in the development of CD8+ T cell responses.

Adoptive Transfer↗

PubMed2003

Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection.

Respiratory dendritic cells (RDC) are believed to play a central role in the induction of adaptive immune responses to pulmonary infection. Herein we examine the basal migration of RDC from the lungs to secondary lymphoid tissues and their enhanced maturation/migration after pulmonary infection/inflammation. We demonstrate that the accelerated migration of RDC to the draining peribronchial lymph nodes occurs only during the first 24 hr after pulmonary virus infection. RDC are refractory to further migration thereafter in spite of ongoing virus replication and pulmonary inflammation. We further demonstrate that induction of this RDC refractory state suppresses additional RDC mobilization to subsequent pulmonary virus infection and results in concomitant suppression of an antiviral pulmonary CD8(+) T cell response.

Animals↗

PubMed2002

On the role of dendritic cells in peripheral T cell tolerance and modulation of autoimmunity.

Recently, it has become clear that dendritic cells (DCs) are essential for the priming of T cell responses. However, their role in the maintenance of peripheral T cell tolerance remains largely undefined. Herein, an antigen-presenting cell (APC) transfer system was devised and applied to experimental allergic encephalomyelitis (EAE), to evaluate the contribution that DCs play in peripheral T cell tolerance. The CD8alpha(-)CD4(+) subset, a minor population among splenic DCs, was found to mediate both tolerance and bystander suppression against diverse T cell specificities. Aggregated (agg) Ig-myelin oligodendrocyte glycoprotein (MOG), an Ig chimera carrying the MOG 35-55 peptide, binds and cross-links FcgammaR on APC leading to efficient peptide presentation and interleukin (IL)-10 production. Furthermore, administration of agg Ig-MOG into diseased mice induces relief from clinical EAE involving multiple epitopes. Such recovery could not occur in FcgammaR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8alpha(-)CD4(+) subset restored Ig-MOG-mediated reversal of EAE. Transfer of CD8alpha(+) or even CD8alpha(-)CD4(-) DCs had no effect on the disease. These findings strongly implicate DCs in peripheral tolerance and emphasize their functional potency, as a small population of DCs was able to support effective suppression of autoimmunity.

Amino Acid Sequence↗