Human CD4+ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

The peripheral repertoire of CD4⁺ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4⁺ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4⁺ lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tm_auto), simulating the circumstances of an active immune response, or allogeneic DCs (Tm_allo). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tm_auto and Tm_allo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tm_allo were closely related to conventional memory lymphocytes based on Erk-1/2 activation, whereas Tm_auto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4⁺ T lymphocytes recognizing self-peptides in the setting of strong costimulation.