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.