An adaptive immune response generates various distinct lineages of memory T (Tmem) cells, which recognize the pathogen and contribute to its clearance. While a substantial proportion of Tmem recirculates, an additional population of CD8+ tissue-resident memory T cells (TRM) infiltrates the affected non-lymphoid tissues and remains lodged therein after infection is resolved. TRM represent a widespread arm of immunity as their existence has been reported in several infectious models and various tissues such as gut, brain, lung, vagina, salivary gland or skin where TRM mediate potent local protective immunity upon secondary infection. As the existence of TRM and their protective function has only been recognised in recent years, the molecular regulation of TRM development and residency remain to be fully elucidated.
Our RNA-microarray analysis of TRM from skin, gut and lung and additional validation via Q-PCR revealed that around 40 genes are selectively up-regulated in TRM versus the circulating Tmem populations. Among others, the core signature contains adhesion molecules and a substantial proportion of genes that are regulated by TGF-ß. Indeed, in vitro stimulation of activated CD8+ T cells with TGF-ß results in the transcriptional up-regulation of a considerable proportion of core signature genes. On the other hand, TGF-ßR2-/- CD8+ are highly impaired in forming TRM. In order to understand how exactly TGF-ß signalling translates into successful TRM development and survival, we have targeted selected candidates of the core signature via RNAi.
We show that TGF-ß is a major driver of TRM development initiating the transcription of a substantial proportion of TRM specific genes. Further study of TRM core genes will expand our understanding of this resident subtype of T cell memory and will eventually aid in our understanding on how to direct vaccination protocols towards focused local responses in barrier tissues.