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.