Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

122 7 Immunosuppresive Factors in Cancer
7.1.2.2 Effects of TGF-b on T lymphocytes
Multiple T cell types, including CD4 + , CD8 + cytolytic T lymphocytes (CTLs) and tumor-infiltrating
lymphocytes (TILs), function as key cellular mediators of the host
immune response to tumors. TGF-b directly suppresses T lymphocyte activity. TGF-b
reduces pore-forming protein expression in human peripheral CD8 + T cells [36], and
inhibits the cytolytic activity of anti-CD3 stimulated CD8 + T cells [37] and of CTLs directed
against fresh tumor targets [38]. Furthermore, TGF-b inhibits the generation of
CTLs in vitro [38]. Similar to its effect on macrophages, TGF-b suppresses cytokine release
by T lymphocytes, including IFN-g, TNF-a, interleukin (IL)-2, IL-6, IL-4 and IL-5
[39±41], which further represses their antitumor activity.
The effects of TGF-b on T cell immune responses are dependent on numerous factors,
including T cell type and activation status. Recently, Ludviksson et al. examined
the effect of TGF-b on T cells (stimulated versus non-stimulated) exhibiting a defined
phenotype [CD4 + versus CD8 + and T helper (Th) 1 versus Th2] and a defined
maturational stage (naÒve versus memory T cells) [42]. They found that:
1. TGF-b inhibits both the proliferation and differentiation of Th1 and Th2 cells, even
when TGF-b is present during primary stimulation.
2. CD4 + T cells primed in the presence of TGF-b exhibit reduced immune responses induced
by receptor cross-linking and/or by specific antigen stimulation which is
independent of co-stimulatory molecule and IL-2 expression.
3. The presence of TGF-b during primary T cell stimulation has a long-lasting or
ªimprintingº effect.
4. The immunosuppressive effects of TGF-b on T cells cannot be reversed with IL-2.
5. TGF-b directly suppresses memory Th1 cytokine production by down-regulating the
IL-12 receptor b2 chain on T cells, while TGF-b has no effect on memory Th2 cytokine
production.
Therefore, tumor-derived TGF-b assists in the escape of tumors from the host cellmediated
immune response by suppressing the host Th1 response and promoting an ineffective
Th2 response.
Similar to its many other activities, the effect of TGF-b on Tcell proliferation is dependent
on the cell population and activation status. In early studies, Kehrl et al. reported
that TGF-b inhibits T cell proliferation [43]. The addition of TGF-b to mixed
lymphocyte tumor cultures results in a decrease in the number of effector CD8 +
CTLs by inhibiting their proliferation [44]. Similarly, TGF-b inhibits the proliferation
of intraepithelial CD8 + lymphocytes following activation [45]. By contrast, when naive
T cells are activated in the presence of TGF-b, they proliferate and secrete IL-2
[46]. The antiproliferative effect of TGF-b has been attributed to down-regulation of
the IL-2 receptor [43, 47] and the inhibition of IL-2 and IL-12-mediated proliferation
signals [48, 49]. IL-2 and IL-12 are immunostimulating cytokines capable of inducing
cytokine production, enhancing cytolytic activity and promoting T cell proliferation.
There are two opposing reports describing the mechanism by which TGF-b inhibits
IL-12-mediated proliferation. Bright et al. showed that TGF-b blocks IL-12 induced
phosphorylation and activation of the Jak-2, Tyk-2 kinases and STAT3 and 4 tran-