Biomedical subjects

Francis R Carbone

Publications and source records attributed to Francis R Carbone.

42 records · Page 3Linked to original sources

PubMed2002

Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells.

Generation of CTL immunity often depends on the availability of CD4 T cell help. In this report, we show that CTL responses induced by cross-priming can be converted from CD4-dependent to CD4-independent by increasing the frequency of CTL precursors. In the absence of CD4 T cells, high numbers of CTL precursors were able to expand in number and become effector CTL. The ability of high frequencies of CD8 T cells to override help was not due to their ability to signal CD40 via expression of CD154. These findings suggest that when precursor frequencies are high, priming of CD8 T cell responses may not require CD4 T cell help.

Animals↗

PubMed2002

Progression of armed CTL from draining lymph node to spleen shortly after localized infection with herpes simplex virus 1.

We have examined the generation of CTL immunity immediately after localized footpad infection with herpes simplex virus 1 (HSV-1) using three coordinated in vivo T cell tracking methodologies. Tetrameric MHC class I containing the immunodominant peptide from HSV-1 glycoprotein B (gB) showed that after infection the proportion of Ag-specific T cells peaked at day 5 within draining popliteal lymph nodes and 2 days later in the spleen. Preferential expression of the activation marker CD25 by tetramer-positive cells in draining popliteal nodes but not spleen suggested that gB-specific T cells were initially activated within the lymph node. In vivo cytotoxicity assays showed that Ag-specific effector cells were present within the draining lymph nodes as early as day 2 after infection, with a further 2-day lag before detection in the spleen. Consistent with the very early arming of effector CTL in the draining lymph node, adoptive transfer of CFSE-labeled gB-specific transgenic T cells showed that they had undergone one to four rounds of cell division by day 2 after infection. In contrast, proliferating T cells were first detected in appreciable numbers in the spleen on day 4, at which time they had undergone extensive cell division. These data demonstrate that HSV-1-specific T cells are rapidly activated and armed within draining lymph nodes shortly after localized HSV-1 infection. This is followed by their dissemination to other compartments such as the spleen, where they further proliferate in an Ag-independent fashion.

Animals↗

PubMed2002

Constitutive, but not inflammatory, cross-presentation is disabled in the pancreas of young mice.

Peripheral antigens can be captured by APC and cross-presented to naive CD8(+) T cells. Notably, cross-presentation of pancreatic antigen is not seen in neonatal mice, although presentation of antigen expressed by the kidney is still intact. In this report, we examined why pancreatic antigens are not cross-presented in neonatal mice. First, we established that antigen expression was not limiting, as neonatal islets expressed as much antigen per cell as adult islets, and vastly more than neonatal renal cells. Next, we analyzed the APC subsets present in the lymph node draining the neonatal pancreas. No obvious population was absent. Finally, we examined whether cross-presentation occurred during inflammation. This showed that inflammation caused by CTL attack of islet tissue facilitated cross-presentation of antigens in neonatal mice. These data indicate that constitutive cross-presentation of islet antigens is inactive during neonatal life, but that under inflammatory conditions this antigen presentation pathway becomes available.

Adoptive Transfer↗

PubMed2002

Characterization of two TCR transgenic mouse lines specific for herpes simplex virus.

To better understand the T cell-mediated processes involved in the immune response to herpes simplex virus type 1 (HSV-1)infection, two HSV-specific T cell receptor (TCR) transgenic mouse lines were produced. These mice (gBT-I.1 and gBT-I.3) are MHC class I-restricted and specific for the immunodominant peptide from HSV glycoprotein B (gB), gB498-505. Although derived from the same clone, the mice differ in the chromosomal location of the TCR transgenes and show marked differences in TCR alpha/beta expression on both CD4+ and CD8+ cells in the thymus. Despite this, peripheral CD8+ Tcells from both mice express equally high levels of the transgenic TCR and bind the KbgB498-505 tetramer to the same degree. In concordance with this, both were shown to respond equally well in vitro upon stimulation with the gB498-505 peptide or HSV-infected cells. These data show that selection of broadly equivalent peripheral T-cell subsets can occur in the presence of distinctly different thymic T-cell subsets.

Amino Acid Sequence↗

PubMed2002

The role of dendritic cell subsets in selection between tolerance and immunity.

Dendritic cells (DC) are considered nature's adjuvants. They are potent stimulators of naive T cells and key inducers of primary immune responses. In recent times it has become clear that they can also play a central role in the development of T cell tolerance. Further complicating our understanding of DC function is the realization that DC can no longer be viewed as a homogeneous cell type. Rather, they exist as a complex mixture of strikingly different cell populations. The mechanisms that drive the conflicting immunological outcomes of tolerance and immunity have been the subject of intense scrutiny in recent years, most recently in terms of how the various DC subsets are involved in these events. Here we review recent experiments that provide insights into how DC subsets control the outcome of T cell activation and in so doing select between immunity and tolerance induction.

Animals↗

PubMed2002

Cross-presentation of antigens by dendritic cells.

T lymphocytes recognize antigen presented on the surface of antigen-presenting cells byMHC class I and class II molecules. Classically, MHC class I molecules present self- or pathogen-derived antigens that are synthesized within the cell, whereas exogenous antigens derived via endocytic uptake are loaded onto MHC class II molecules for presentation to CD4+ T cells. It is becoming increasingly clear that some dendritic cells are also specialized to process exogenous antigens into the MHC class I pathway for presentation to CD8+ T cells. This process is known as cross-presentation. It provides a mechanism that can drive dendritic cells to generate either tolerance to self-antigens or immunity to pathogens. The cells responsible for, and mechanisms underlying, this decision between tolerance and immunity via cross-presentation has become the focus of intense study to determine how various dendritic cell subsets effect the different outcomes.

Animals↗