Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Functional impairment and phenotypic shift of natural and induced regulatory T cell in early development of Type 1 Diabetes in an experimental model (#187)

Kailash Singh 1 , Erik Kadesjö 1 , Julia Lindroos 1 , Marcus Hjort 1 , Stellan Sandler 1 , Lina Thorvaldson 1
  1. Uppsala University, Uppsala, Sweden

Despite intense research on the role of the regulatory T cells (Treg) in the last decades, the kinetics of regulatory T cells in the early development of type 1 diabetes (T1D) is still not clear.
We have examined the proportions of CD4+CD25+Foxp3+Helios+ natural Treg (nTreg), CD4+CD25+Foxp3+Helios- induced Treg (iTreg) and CD4+ T helper (Th) cells at close intervals in the multiple low dose streptozotocin (MLDSTZ) murine T1D model.

The Foxp3 mRNA levels were significantly elevated in the spleen, pancreas and PDLNs of MLDSTZ treated mice. Foxp3 immunostaining in pancreas and spleen suggested that the infiltration of Treg cells increased in islets of Langerhans, exocrine pancreas and spleen of MLDSTZ treated. The proportions of Treg cells were increased in MLDSTZ treated mice from day 7 in the pancreatic draining lymph nodes (PDLNs) and from day 21 in spleen.

The proportions of CD4+CD25- Th cells in MLDSTZ treated mice decreased on day 7, but increase from day 10, suggesting that the increase in Tregs fail to control the ongoing immune insult. Impaired mRNA expression levels of IL-35 and IL-10 in PDLNs and spleen of MLDSTZ suggest a functional impairment of the Tregs. Furthermore, increased IFN-g co-expressing nTregs and iTreg in MLDSTZ mice suggested a phenotypic shift in upregulated Tregs. Moreover, inherently bifunctional CD4+CD25+Foxp3+Eos-CD38+ Tregs were also increased in MLDSTZ mice. Suggesting that acquisition of effector cell phenotype in increased Treg is due this subpopulation of Treg.
Thus, nTregs and iTregs are upregulated in the development of MLDSTZ. However, the upregulation does not protect from hyperglycemia, possibly because of a functional deficiency due to impaired IL-35 and phenotypic shift in the nTreg and iTreg population in MLDSTZ treated mice.