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McGuinness andArceci 637
modified malignant cells. 24-28
The exact mechanism for the recruitment and
expansion of these T cell subsets by different cytokines is still uncertain, although
several critical observations concerning antigen recognition and T cell activation
have provided some important clues.
The process by which T cells become activated by antigen presenting cells
(APCs) depends on 1) T cell receptor (TCR) recognition of antigen and signaling
through the TCR (signal 1) and 2) a costimulatory signal involving specific cell
surface receptors on APCs and T cells (signal 2) followed by the induction of
interleukin (IL)-2 and its receptor (IL-2R) by T cells, resulting in their proliferation
and function. 29-31
A wide variety of surface molecules have been identified that are
involved in the costimulatory second signal of the T cell response. 29-31
One particularly
important costimulation pathway involves the B7 family of APC surface
molecules including at least B711 (CD80) and B712 (CD86) and their T cell
receptors, CD28 and CTLA-4. 29-32
Although CTLA-4 has a higher affinity for
CD80 and CD86 than CD28, it is not a strictly redundant pathway, as it does not
compensate for the lack of CD28-mediated costimulation in CD28
knockout/deficient mice. 33
Instead, engagement of the CTLA-4 receptor exerts a
significant downregulatory effect on T cell activation both in vitro and in vivo. 34
Linsley et al. constructed an important reagent by fusing the extracellular domain
of CTLA-4 and the human Ig C7I chain. 35
This reagent has the ability to
effectively and specifically block CD80/CD28 costimulatory signaling. 35
Several recent studies have elegantly demonstrated the central importance of the
B7 pathway in tumor-mediated costimulation. 30,34
' 36-41
Based on these
observations, it has been hypothesized that tumor cells may escape immune
recognition and killing by failing to satisfy the above requirements for T cell
antigen recognition and activation. 29-32
For example, if antigen recognition occurs
but tumor cells do not express a costimulatory molecule, then T cells may develop
anergy or tolerance to the tumor cells. This situation has been experimentally
observed in animal tumor models as well as in some human malignancies. 29-32
Thus, potential strategies for eliciting specific antitumor T cell responses have
included attempts to express costimulatory surface receptors by gene transfer into
tumors which otherwise do not express them, thereby supplying the critical costimulation
signal for T cell activation. This second approach has been shown to work
in several different animal tumor models, particularly ones involving melanomas,
lymphomas, and murine sarcomas. 30,34,36-41
Recent studies, including those from our own laboratory, have demonstrated a
critical role for CD80-mediated costimulation in the generation of antileukemic
immune responses. 42
^ 14
This work has shown that retroviral transduction of B7-1
cDNA into unselected leukemia cells is able to induce a specific antileukemic
response even against unmodified, preexisting leukemia. The antileukemic activity
is primarily due to a CD8 +
cytolytic T lymphocyte (CTL) response to an as-yet-