SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8⁺ T cells

The prevailing 'division of labor' concept in cellular immunity is that CD8⁺ T cells primarily utilize cytotoxic functions to kill target cells, while CD4⁺ T cells exert helper/inducer functions. Multiple subsets of CD4⁺ memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8⁺ memory T-cell subsets exist, characterized by identical chemokine receptor expression signatures and controlled by similar generic programs. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17 + 1 cells, express IL-6R but not SLAMF7, completely lack cytotoxicity and instead display helper functions including CD40L expression. CD8⁺ helper T cells exhibit a unique TCR repertoire, express genes related to skin resident memory T cells (T_RM) and are altered in the inflammatory skin disease psoriasis. Our findings reveal that the conventional view of CD4⁺ and CD8⁺ T cell capabilities and functions in human health and disease needs to be revised.