Human T1D pancreatic lymph nodes contain diabetes-autoantigen responsive T cells but identification of such T cells in the periphery has proven difficult. Here we describe a unique T cell subset defined by CD4(lo) and CD40 expression (T(CD40)) that is significantly expanded in peripheral blood of T1D but not control or T2D subjects. The HLA-DR3 and DR4 alleles are considered high risk factors for T1D and T(CD40) expansion occurs in T1D subjects carrying HLA DR3 or DR4 haplotypes but, T1D subjects who do not carry either DR3 or DR4 haplotypes still have an expanded percentage of T(CD40) cells. Non-autoimmune subjects, even DR3(+) and DR4(+), do not have elevated percentages of T(CD40) cells. The majority of T(CD40) cells in T1D carry a memory phenotype and a portion of those proliferates when exposed to diabetes-associated self-antigens. A greater number of memory T(CD40) cells express CXCR3 when compared to CD40(-) memory cells and that number is significantly expanded in T1D compared to control subjects. If only total CD4(+) T cells are compared no difference in CXCR3 is seen. Furthermore, T(CD40) cells produce a Th1, pro-inflammatory cytokine profile. In healthy controls, T(CD40) cells have equally Th1 and Th2 profiles.