Generation and homeostatic regulation of CD8αβ effector memory T cells by CD8αα and its ligand, the thymic leukemia (TL) antigen

Abstract

Abundant intra‐epithelial lymphocytes (IEL) reside within the intestinal epithelium making the intestinal IELs the largest T cell population in the body. The majority of CD8αβ T cell subset of intestinal IELs displays an effector memory phenotype. These experienced T cells populate the mucosal surface and provide rapid and efficient immune protection at the largest entry surface for pathogens. The conditions that lead to mucosal effector memory differentiation are poorly understood. We found that CD8αβ effector memory IELs are derived preferentially from primary effector cells that transiently induce CD8ααduring the effector phase. CD8αα not only plays a key role in this memory differentiation process, but it is also required for long‐term survival of CD8αβ+ effector memory IELs. TL, as a ligand for CD8αα, is not required for the generation or survival of CD8αβ effector memory IELs. Surprisingly however, TL expressed by the intestinal epithelial cells causes death of activated CD8αβ T cells. On the other hand, when interacting with TL, CD8αα rescues activated CD8αβ IEL from cell death induced by TL. Here we provide the first evidence that a unique memory process exists that leads to the specific differentiation of mucosal effector memory T cells that gain the capacity to reside long term at the mucosal surface where they provide immediate and highly effective immune responses upon re‐challenge.