Single-cell dynamics of T-cell priming
Sarah E Henrickson and Ulrich H von Andrian
The recent application of in vivo imaging to characterize the
dynamics of T-cell activation by dendritic cells (DCs) has
reshaped long-held beliefs of how adaptive immune responses
are initiated. However, to improve our fundamental
understanding, these new observations must be synthesized
with the diverse theories and paradigms in the field, many of
which were established before the advent of the cutting-edge
techniques in a modern immunologist’s toolbox. A number of
factors have been investigated that combine to determine the
ability of the DC to activate a naı
¨
ve T cell: the rules that govern
the ability of a T cell to find antigen-bearing DCs; the
parameters that define the dose and quality of the antigenic
signal; and the mechanisms used by the T cell to interpret a
given antigenic signal. Considering T-cell activation to be
determined by the sum of interdependent factors might allow
us to integrate seemingly disparate observations and
hypotheses and to formulate testable predictions for further
experimentation.
Addresses
Department of Pathology, Harvard Medical School, 77 Avenue Louis
Pasteur, Boston, MA 02115, USA
Corresponding author: von Andrian, Ulrich H (uva@hms.harvard.edu)
Current Opinion in Immunology 2007, 19:249–258
This review comes from a themed issue on
Lymphocyte activation
Edited by Ulrich von Andrian and Federica Sallusto
Available online 12th April 2007
0952-7915/$ – see front matter
# 2007 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2007.04.013
Introduction
Naı
¨
ve T cells are activated by interactions with antigen-
presenting cells (APCs), usually dendritic cells (DCs), in
secondary lymphoid organs (SLOs) [1]. To give rise to
effector cells, T cells must be exposed to more than one
activation signal [2], comprised of a peptide–MHC
(pMHC) complex (the antigen) that stimulates the
T-cell receptor (TCR) [3] as well as costimulation by
B7 family members that bind to CD28 expressed on T
cells [4]. T cells are also influenced by cytokine signals
from the environment [5]. In this article, we review our
current understanding of how interactions with DCs
provide these prerequisite signals to T cells, how these
interactions change over time, and how they might be
regulated. We will specifically focus on the parameters
that determine how information between T cells and DCs
is exchanged. What controls the ability of T cells to find
and contact DCs? How are antigenic signals communi-
cated to T cells by DCs? What determines how T cells
interpret such antigenic signals?
At the outset, it is important to note that the requirements
for effective activation are distinct for different T-cell
subsets, including CD4 versus CD8 T cells. The latter
can commit to a program of proliferation and effector/
memory differentiation after only short-term stimulation
in the presence of appropriate cytokines [6]. By contrast,
CD4 T cells need constant antigenic stimulation for
sustained proliferation [7], although shorter stimulation
might suffice in some settings [8]. In addition, the kinetics
and consequences of T-cell activation are critically deter-
mined by initial assay conditions, such as the nature of the
activating signal (e.g. chemicals such as phorbol esters
and/or calcium ionophores, antibodies, mitogens, super-
antigens, pMHC complexes or proteins presented by
professional or non-professional APCs), the prior history
of the T cells (e.g. naı
¨
ve versus resting memory versus
proliferating, primary effector versus cell line) and the
environment (e.g. immobilized ligands on two-dimen-
sional surfaces or in three-dimensional gels, explanted
tissues or whole animals, SLOs or non-lymphoid tissues).
Unfortunately, there are no uniformly standardized con-
ditions; this adds considerable complexity to any attempt
to make sense of the current literature.
Beyond the issue of experimental conditions, there is also
great diversity in the selection of assays used to measure
T-cell activation. Commonly acquired parameters
include: intracellular calcium flux; the (sometimes tran-
sient) induction of activation markers; T-cell proliferation
(measured by various techniques); cytokine production;
cytotoxicity; and memory cell differentiation and/or sur-
vival. All these approaches have merit, in that each
measures a viable consequence of T-cell activation, but
different activating stimuli can vary substantially with
regard to the magnitude and kinetics at which they
modulate individual activation parameters. With these
caveats in mind, this review will attempt to bring together
a broad sampling of the current literature. We will prim-
arily concentrate on our understanding of the events that
occur during activation of naı
¨
ve CD8 T cells by DCs that
present cognate pMHC.
How to study T-cell priming in vivo
As only few naı
¨
ve T cells can recognize any given epitope
(1in10
6
–10
7
), each antigen-bearing DC must interact
with many T cells in the hope of being found by a T cell
that recognizes a cognate antigen on its surface. The rules
www.sciencedirect.com Current Opinion in Immunology 2007, 19:249–258