A unique T cell subset described as CD4^loCD40⁺ T cells (T_CD40) in human type 1 diabetes

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.