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10.991 Student Seminar
December 1, 2008
Signal Integration in Immune Cell Biology
Kevin Fowler
Thesis Advisor: Arup Chakraborty
The adaptive immune response allows the body to protect itself from a diverse set of
pathogens. Key orchestrators of the adaptive immune response are T cells which
recognize antigen through interactions between their T cell receptor (TCR) and antigen
presenting cells. The TCR intracellular signaling pathway is well understood and past
members of our group have successfully developed mathematical models to study T cell
activation. One potential limitation of models that only consider the TCR pathway is that
T cells receive numerous signals from various sources including cytokines and
costimulatory molecules. The focus of my research is to determine how T cells integrate
these various signals and how that affects the nature of the immune response.
To approach the problem of how T cells integrate various cytokine signals with the TCR
pathway, we first needed to be able to model cytokine signaling alone. As a case study,
we considered the cytokines, IL-6 and IL-10. Though these two cytokines activate
primarily the same transcription factor, IL-6 is pro-inflammatory, while IL-10 is antiinflammatory. One major difference between the two is that IL-6 induces a transient
signal, while IL-10 induces a sustained signal. We propose a simple transcriptional
network that can be activated by a single transcription factor, but that leads to two
different cellular decisions based entirely on the duration of the signal. We find that the
network is not sensitive to moderate changes in the amplitude of the signal.
We then consider how cytokine signals are integrated by studying the differentiation of
naïve T cells into either regulatory T cells (Tregs) or into the recently discovered Th17
lineage, which induces inflammation and has been implicated in autoimmune diseases
including multiple sclerosis. The exposure of naïve T cells to TGF-β leads to the Treg
lineage, while exposure to TGF-β and IL-6 leads to Th17 cells. Thus, the development of
these two very different lineages differs only by the addition of IL-6. Our signal duration
model may provide insight into how the IL-6 and TGF-β signals are integrated and
therefore our initial experiments have been geared towards quantifying both the
amplitude and duration of these signals.