Download Enhancement of CD154/IL4 Proliferation by the T

Enhancement of CD154/IL4 Proliferation by the T follicular helper (Tfh) cytokine, IL21 and
increased numbers of circulating cells resembling Tfh cells in CLL.
Ahearne et al. BJH2013 May 27. doi: 10.1111/bjh.12401. [Epub ahead of print]
Despite not being part of the malignant clone, abnormalities in T cell numbers and function
are well described features of CLL. Within the lymph node microenvironment, activated
CD4+CD25+ T cells have been shown to be in close vicinity to proliferating tumour cells and
in-vitro co-culture of CLL cells with autologous activated T cells can induce proliferation and
survival of the CLL B cells. Therefore, blocking T cell/CLL cell interactions and the cytokines
secreted is an appealing therapeutic strategy for this largely incurable disease. However, in
order for such therapies to be developed, it is essential for the biology of the CLL
microenvironment, in particular that of the role of T cells and their cytokines, to be better
understood.
The recently described T cell subset, Follicular helper T cells (Tfh), has emerged as the
major class of IL-4 and IL-21 producing T cells in the lymph node. IL-4 is known to promote
the survival and proliferation of CLL cells. In contrast, the effect of IL-21 as a single agent in
CLL has previously been shown to be pro-apoptotic and for this reason has been considered
as a therapy for CLL. In this study by Ahearne et al, the effect of the combination of IL-4 and
IL-21, as secreted by Tfh cells, is studied and shown to enhance the proliferation (thymidine
and BrdU incorporation) of activated CLL cells. This activation is to a level over and above
that of IL-4 alone. Furthermore, this study demonstrates that CLL cell proliferation is
enhanced further when the IL-21 is added sequentially 24 hours after IL-4 and sCD154
stimulation and that this additional effect of IL-21 is exerted through the phosphorylation of
STAT-3. STAT-3 is a transcription activator known to play a role in oncogenesis.
Interestingly, in combination with IL-4, IL-21 does not induce apoptosis. These findings alone
provide a strong case to oppose the use of IL-21 as a therapy for CLL. However,
additionally, the authors demonstrate that the addition of IL-21 to activated CLL cells in a 36hour culture increases the number of chemoresistant side population cells.
Following their study into the effect of the Tfh cytokine secretions on CLL, the authors looked
at the numbers of Tfh cells in patients with CLL. Using traditional single label
immunohistochemistry the authors demonstrated PD-1 and IL-21 expression individually in
CLL lymph nodes but, as this staining was not done in combination with any other markers, it
is impossible to know the phenotypic nature of the positive cells. This remains an area that
needs to be studied further. However, the authors did do a more comprehensive study on
circulating Tfh cells in CLL and demonstrated that these patients have higher levels of
CD4+CXCR5hiICOShi than age matched normal controls. Interestingly, there was no
association between Tfh numbers in CLL with the prognostic markers IGVH gene mutational
status, serum lactate dehydrogenase and surprisingly, lymphocyte doubling time.
Unfortunately, association with CD38 status was not analysed and as CD38 is a marker of
activation and proliferation this would have been an interesting observation.
This timely study further emphasizes the important role of T cell subsets and the cytokines
they produce in the survival and proliferation of CLL. In addition, it raises the important issue
of cytokines behaving in totally opposing directions when in combination with other cytokines
as opposed to alone. The role of Tfh in CLL and their promotion of chemoresistant tumour
cells is an area that needs to be further explored and hopefully such explorations will result
in therapies targeting these interactions.
Andrea Buggins, King’s College London, July 2013.