Arrieta Bolanos, ER; Madrigal, J; Shaw, B; (2012) Functional consequences of TGFB1 polymorphisms in regulatory T cells and haematopoietic stem cell transplantation. Presented at: The Joint 16th International HLA and Immunogenetics Conference/26th European Immunogenetics and Histocompatibility Conference/23rd British Society of Histocompatibilty and Immunogenetics Conference, Liverpool, UK.

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Abstract

Haematopoietic stem cell transplantation (HSCT) is used to treat malignant and non- malignant diseases. Apart from clinical and HLA-related factors, non-HLA Immunogenetics is being increasingly recognized to play a role in the outcome of HSCT. A gene that may be relevant for the outcome of HSCT is TGFB1, which encodes Transforming Growth Factor β 1 (TGF-β1), a cytokine that is central in the regulation of numerous immune processes. Several polymorphisms in TGFB1 have been identified and some of them are known to cause alterations in cytokine secretion. We and others have previously shown that polymorphisms within TGFB1 affect the outcome of HSCT. Regulatory T cells (Treg) are major producers of TGF-β1 and play a fundamental role in immune events in HSCT. Consequently, we have studied the effect of TGFB1 polymorphisms on the function of Treg and their role in HSCT complications such as GVHD. Molecular typing techniques for the detection of TGFB1 +29T>C SNP have been employed to type 31 healthy blood donors recruited for functional experiments. Membrane-bound TGF-β1 (LAP positivity) upon TCR stimulation of isolated Treg has been assessed in 5 donors per TGFB1 +29T>C genotype. The in vitro kinetics of TGF-β1 induction on these cells after TCR stimulation with soluble antibodies against CD3 and CD28 was shown to peak at 24h of incubation and to reach an average of 25.7% of the CD4+CD25++CD127lo cells (range 11.0-51.2%), followed by a reduction to low levels by 48h, which remain constant up to 96h. A trend towards a higher percentage of LAP+ Treg generated after activation when the cells bear a +29C allele (Pro10 on its signal peptide) was identified (p=0.066). Higher or lower production of TGF-β1 by Treg in the inflammatory context of HSCT may influence the development of GVHD. We are currently conducting real-time PCR experiments and optimized suppression assays in order to fully evaluate the role of this and other TGFB1 polymorphisms on Treg function and its meaning for HSCT.

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