CD4 T Cells Acquire Innate Capability Upon Classical T Cell Activation

Memory T cells, a sizable compartment of the mature immune system, enable enhanced responses upon re-infection with the same pathogen. We have recently shown that virus-experienced innate acting T (T_IA) cells can modulate infectious or autoimmune diseases through TCR-independent IFN-γ production. However, how these cells arise remains unclear. Here, we show that CD4 T_IA cells are present in various disease settings hinting towards a disease-agnostic nature. TCR stimulation and CD28 co-stimulation are sufficient to induce naïve murine and human CD4 T cells to become capable of cytokine-mediated, TCR-independent IFN-γ responses. In true T_IA fashion, adoptive transfer of in vitro-induced T_IA cells in mice yielded a TCR-independent IFN-γ response during the innate phase of a Legionella pneumophila infection. Our data thus shows that CD4 T_IA cells are more ubiquitous than anticipated and could therefore be involved in more settings than expected.