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Sytze de Roock

Wednesday 11 January 2012

Immune regulation in gut and cord; opportunities for directing the immune system

Promotor: Prof.dr A.B.J. Prakken
Defence: 22 March 2012

Summary
The gut is an important organ for the immune system. Microbes and immune cells interact directly or via epithelial cells. Both TH17 and Treg cells mature in this environment. The composition of the microbiota has an important influence on the immune homeostasis. Influencing the immune system via the microbiota has been a challenge for scientist and clinicians for several decades. Especially atopic disorders like asthma and eczema have been subject to prophylactic trials with probiotics, with disappointing results however.
We hypothesized an important role for bacterial species in the immune regulating effect of probiotics. We tested a large number of gut derived lactic acid bacterial strains for there in vitro immune regulating properties using several techniques. All known subsets of CD4+ T cells (TH1, TH2, TH17 and regulatory T cells) could be induced by these bacteria, showing that probiotics can direct the immune system in different directions. These findings show that careful selection of a strain prior to clinical application is needed in order to select the appropriate strain for an immunological purpose. Some strains show to be potent inducers of functional FOXP3+ regulatory T cells (Treg). These Treg are induced de novo from CD25- T cells, without a dependency on IL-10. The effect of strains showed to be donor dependent, which implies that different strains will be beneficial for each individual.
The effect of probiotic supplementation has been shown by others to be most effective early in life. We hypothesized that the neonatal naive immune system is more prone to produce Treg than the adult counterpart, resulting in immune regulation rather than immune activation. In order to test this, we compared cord blood (CB) and adult peripheral blood (APB) derived naive T cells after activation with anti-CD3. Indeed, CB T cells became FOXP3+ more easily than APB T cells. This effect was critically dependent on the interaction between antigen presenting cells (APC) and T cells; removal of APC from the cultures reduced the effect. Moreover, blockade of the interaction between the molecules programmed death (PD)-1 and its ligand PD-L1 expressed by T cells and APC respectively significantly reduced the induction (of differentiation to) of FOXP3+ Treg.
The ability to differentiate into TH17 cells is affected in CB as well; anti-CD3 activation of APB cells induced IL-17 producing T cells, but CB cells were unable to do so. Interleukin (IL)-1β, IL-6 and IL-23 are known to positively influence the induction of TH17 cells; addition of these cytokines resulted in more IL-17 production by APB cells, but had no effect on CB cells. Nevertheless, FOXP3+ cell number in CB cell cultures was reduced by these cytokines. This finding shows that another factor affects the possibility of naive T cells to differentiate in either an inflammatory TH17 cell or a regulatory Treg. This T cell intrinsic factor could show to be a future target for directing the immune system towards inflammation or regulation.


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