Evidence is accumulating that the progressive aspects of bovine paratuberculosis are related to a shift from a T1, cell mediated, to a T2, humoral, type of immune response. We have studied the cellular and humoral responses in paratuberculous cattle to a number of mycobacterial antigens regarding the T1 to T2 shift during the progression of the disease, and the role of activation induced cell death (AICD) in this switch. In 150 animals in different stages of paratuberculosis lymphocyte proliferation assays and ELISA were used to evaluate responses to different PPD's, the 65 and 70 kD recombinant mycobacterial heat shock proteins, and lipoarabinnomannan (LAM) antigens. In an additional 20 animals local gastrointestinal responses to the same antigens using the same techniques, in addition cytokine mRNA levels were evaluated and compared to what was found in peripheral blood. In vitro cultures of (un)infected bovine monocyte derived macrophages and T cells, and the TUNEL assay were used to evaluate AICD. The results indicate that a T1 to T2 shift appears to take place during the disease but that, especially with regard to the humoral responses, the type of antigen and its putative predominant localisation during the infection play a major role in both the direction and magnitude of the switch. Furthermore we have found indications that AICD of T cells caused by chronically infected macrophages in situ may be a possible mechanism for this T1 to T2 switch during bovine paratuberculosis.