Tissue instruction for migration and retention of TRM cells

• Effector T cells receive tissues instructions and establish long-term residency.
• TRM are more protective than circulating memory cells based on their location and function.
• Epithelial TRM cells express CD103 and shut off S1P1 and CCR7 to prevent egress.
• Memory lymphocyte clusters (MLCs) retain CD103neg CD4 and CD8 TRM in the lamina priopria.

During infection, a subset of effector T cells seeds the lymphoid and non-lymphoid tissues and gives rise to tissue-resident memory T cells (TRM). Recent findings have provided insight into the molecular and cellular mechanisms underlying tissue instruction of TRM cell homing, as well as the programs involved in their retention and maintenance. We review these findings here, highlighting both common features and distinctions between CD4 TRM and CD8 TRM cells. In this context we examine the role of memory lymphocyte clusters (MLCs), and propose that the MLCs serve as an immediate response center consisting of TRM cells on standby, capable of detecting incoming pathogens and mounting robust local immune responses to contain and limit the spread of infectious agents.