Background/Aims: It has been suggested that diabetes is associated with immune dysfunction, in which Ca2+ signaling malfunction in lymphocyte may contributes most. However, the pattern of the Ca2+ signal disorder and the mechanism(s) that explains the change are unclear. Here, in this study we aimed to investigate possible changes and mechanism(s) accounting for the internal Ca2+ signals in diabetic T lymphocyte upon stimulation. Methods and results: Using Fura-2-AM, we found a significant decrease in Ca2+ influx induced by thapsigargin (TG) and anti-CD3 antibody (OKT3) in T lymphocytes from blood of both diabetes patients and animals. Furthermore, a downregulated Orai1 protein expression, but not mRNA, was also observed in these cells using western blot and qRT-PCR, respectively. In addition, in high-glucose and agonist treated Jurkat T cells, Ca2+ entry and the release of interleukin-2 (IL-2) were also decreased. Orai1 expression reduced, while stromal interaction molecule 1 (STIM1) and other downstream proteins remained unchanged. Conclusion: This study demonstrates that the declined Orai1 expression, at least partly, contributes to the downregulated Ca2+ entry during lymphocyte excitation, providing an important mechanism for T lymphocyte malfunction in diabetes. (C) 2018 Elsevier Inc. All rights reserved.