Recent studies suggest a beneficial role for blocking CD103 signaling in preventing islet allograft rejection and thus Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. However, antibody blockade approaches generally raise anti-microbial safety issues, necessitating additional studies to address the possible adverse effects of antibody therapy. Here we report that CD103 had no significant impact on the development of primary and memory CD8(+) or CD4(+) responses after acute lymphocytic choriomeningitis virus (LCMV) infection. In addition, CD103 was found to be dispensable for T1D progression in a rapid, CD8-mediated virally-induced T1D model (the rat insulin promoter [RIP]-LCMV), suggesting that its previous efficacy in the NOD mouse model may not be related to its effect on the generation, memory conversion and/or effector function of CD8(+) or CD4(+) T cells. While the data does not preclude a role for CD103 in T1D in its entirety, the current study does provide much evidence to suggest that CD103 blockade may prove to be a safe intervention for autoimmunity and allo-transplantation. While in cases of rapid microbial (CD8)-driven T1D CD103 antibody blockade may not limit disease progression or severity, in mucosally-driven cases of T1D anti-CD103 antibody treatment may provide a new and safe therapeutic avenue.