Inmunidad Cd8

Immunity

Review
CD8+ T Cells: Foot Soldiers of the Immune System
Nu Zhang1,* and Michael J. Bevan1,*
1Department of Immunology and the Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
*Correspondence: nuz@uw.edu (N.Z.), mbevan@uw.edu (M.J.B.)
DOI 10.1016/j.immuni.2011.07.010

Resting naive CD8+ T cells have an astounding capacity to react to pathogensby massive expansion and
differentiation into cytotoxic effector cells that migrate to all corners of the body to clear the infection. The
initial interaction with antigen-presenting cells in the central lymphoid organs drives an orchestrated program
of differentiation aimed at producing sufficient numbers of effectors to get the job done without resulting
in clonal exhaustion. Interactionswith antigen-presenting cells and other immune cells continue at the site
of infection to regulate further on-site expansion and differentiation, all with the goal of protecting the host
with minimal bystander tissue damage. Here we review recent advances in CD8+ T cell recognition of antigen
in lymphoid as well as in nonlymphoid tissues in the periphery, and how CD8+ T cell expansion anddifferentiation are controlled in these contexts.
Introduction to Cytotoxic T Cells
Much of the early work that would eventually lead to the recognition of antigen-specific cell-mediated lysis of target cells relied
on allogeneic, MHC-disparate tissue and tumor transplantation
models and allogeneic mixed lymphocyte cultures. In many of
these systems, a subset of thymus-derived T lymphocytes withclonally distributed receptors was shown to be responsible for
in vitro cell-mediated lysis of target cells (Cantor and Boyse,
1975; Cerottini et al., 1970; Golstein et al., 1972). However, it
was work in a syngeneic system with lymphocytic choriomeningitis virus (LCMV)-infected mice that revealed the dual specificity
of specific T lymphocytes for viral antigen plus self-MHC that explained theinvolvement of MHC class I molecules with CD8+
T cell recognition of antigen and introduced the notion of ‘‘altered
self’’ (Zinkernagel and Doherty, 1974). Just how readily viruses
and other infections stimulate potent cytotoxic T lymphocyte
(CTL) responses is illustrated by human cases of acute infectious
mononucleosis or ‘‘kissing disease’’ caused by exposure to the
Epstein-Barr gammaherpes virus (EBV). The disease is characterized by swollen lymph nodes and a remarkable rise in the
number of peripheral blood monocytes. In fact the bulk of the
monocytosis turns out to be a lymphocytosis consisting mostly
of activated CD8+ CTL with specificity for EBV peptides (Callan
et al., 1996). The response to EBV provides a remarkable example of the magnitude of the proliferative burst ofclones of
antigen-specific CD8+ lymphocytes in response to an infectious
agent. Similarly, it had been realized for many years that infection
of mice with LCMV led to an inversion of the CD4:CD8 ratio
because of a dramatic increase in CD8+ T cell numbers but it
was not until tetramer staining or the adoptive transfer of small
numbers of TCR transgenic CD8+ T cells was employed that it
wasrealized that the bulk of the CD8+ expansion was due to
antigen-driven proliferation (Butz and Bevan, 1998; MuraliKrishna et al., 1998). During many infections, all T lymphocytes
regardless of specificity may undergo cytokine-driven phenotypic changes—so-called bystander activation—but only those
T cells that recognize pathogen-encoded antigen go through
multiple rounds of replication togenerate enormous numbers
of CTL effector progeny that are the foot soldiers of the adaptive
immune response.

Recruiting: Initial CD8+ T Cell Activation
During an infection, naive CD8+ T cells are primed by antigenpresenting cells (APCs) in secondary lymphoid organs such as
lymph nodes (LN) and spleen. How are the CD8+ T cells activated
by the APCs? Seeing is believing. The application of...