Figure 2. CD4 T_EM cells as potential mediators of ICI-induced irAEs.

CD4 T_EM cells may traffic to sites of future toxicity from the peripheral blood, then directly or indirectly contribute to irAE etiology via several scenarios, including 1) direct TCR-mediated cytotoxicity, 2) activation of tissue-resident CD8 memory T cells (CD8 T_RM) that drive toxicity, or 3) activation of myeloid cells that exert tissue toxicity through innate proinflammatory programs or further activation of cytotoxic T cells. Alternatively, CD4 T_EM cells may not be directly involved in irAE development but may instead represent a circulating biomarker with a different upstream mediator responsible for direct tissue toxicity.