The development of arthritis, psoriasis-like skin inflammation and ileitis in the microbial β-glucan (curdlan) induced BALB/c ZAP70^W163C mutant (SKG) mouse, is characterized by an overwhelming increase of auto-reactive CD4+ T cells in the peripheral organs. However, the mechanism how this systemic adjuvant promotes T-cell-mediated chronic tissue inflammation in SKG mice but not in BALB/c mice is not fully understood. To elucidate the dynamics of post-curdlan CD4+ T cells expansion and regulation, syngeneic luciferase-expressing CD4+ T cells were adoptively transferred, and tracked in vivo in SKG and BALB/c mice. Bioluminescent images showed an increased CD4+ T cell accumulation in spleen and inguinal lymph nodes 3 days after curdlan, followed by focal signals from the ankles with traffic to joints, tail, and ears at day 7, and continued to expand in SKG hosts. Signals from transferred SKG T cells increased at low level in spleen of curdlan-treated BALB/c recipients at day 7, but subsequently disappeared. However, T cells expanding in SKG mice are more likely to produce IL-17 with a reduced frequency of Tr1 (Foxp3-IL-10+IFNg+) cells, even after curdlan treatment, than its wildtype BALB/c counterparts. However, in vitro induction of naïve SKG CD4+ T cells into Tr1 cells by IL-27 was as efficient as BALB/c cells, indicating a deficiency of IL-27 mediated development of Tr1 cells in SKG mice. These data show that autoreactive SKG T cells spontaneously expand in lymphoid organs with tissue infiltration in SKG mice, but is strongly restrained in BALB/c hosts. Thus, peripheral Tr1 cell deficiency in SKG mice due to ZAP-70 signaling defect resulting in poor control of autoreactive T cell expansion suggests an absence of peripheral tolerance in SKG hosts.