During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also "stochastic," since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts.