Differentiation of naïve into memory-phenotype CD8 ⁺ T cells does not promote the breakdown of peripheral tolerance in irradiated mice

Lymphodepletion, which is currently used as adjuvant for adoptive cytotoxic T cell immunotherapy in cancer, promotes the breakdown of peripheral CD8 ⁺ T cell tolerance. Under lymphopenic conditions, naive T cells proliferate due to a greater availability of homeostatic cues. Proliferating CD8 ⁺ T cells acquire a phenotype and functionality that is similar to memory cells and are termed memory-like cells. Since memory cells are thought to have a lower activation threshold than naïve cells, it has been proposed that differentiation of potentially autoreactive CD8 ⁺ T cells into memory-like cells could drive the breakdown of tolerance under lymphopenic conditions. Here we studied whether lymphopenia induced proliferation and differentiation are required to overcome CD8 ⁺ T cell cross-tolerance in irradiated mice. Surprisingly, we found that blocking homeostatic proliferation by IL-7 neutralization did not prevent self-reactivity. CD8 ⁺ T cells that remained in a naïve state still became effectors upon antigen cross-presentation as efficiently as memory-like cells. Nonetheless, lymphopenia induced proliferation did enhance CD8 ⁺ T cell mediated self-reactivity at low T cell frequencies by increasing autoreactive T cell numbers. Thus, although homeostatic proliferation enhances CD8 ⁺ T cell anti-self responses, differentiation into memory-like cells is not essential for the breakdown of cross-tolerance after irradiation.