Memory is a trademark of adaptive immunity. Tissue resident memory (TRM) cells are a newly identified subset of CD8+ (cytotoxic) T cells found to be disconnected from circulation and localized permanently in peripheral tissues such as skin, lung, gut, brain, and female genital tract after an infection. TRMs are a phenotypically and functionally distinct population, which distinguishes them from the well-known recirculating memory subsets, the central memory T cells (TCM) and the effector memory T cells (TEM) cells.
In order to elucidate the molecular signature that distinguishes the TRMs from the TCM and TEM populations, we compared the expression profiles of CD8+ TRMs isolated from mouse brain, lung, gut and skin to the circulating memory pool from spleen following an acute viral infection. To further characterize the transcriptional network that governs the differentiation of TRMs, we selected the 2,197 differentially expressed genes between the resident and circulation memory cells and clustered them using a differential co-expression network based approach to identify gene sub-network that are differentially co-expressed between these two groups. We found that one sub-network in particular (“resident module”) was highly co-expressed in the resident but not circulating memory T Cells. To elucidate the biological processes associated with resident module, functional enrichment analysis was carried out to identify statistically significant enrichment of common functional pathways and gene ontology descriptions. We found that resident module was enriched for genes involved in cytokine-cytokine receptor interaction, T cell receptor signalling and MAPK signalling. This shows that TRMs harbour a distinct transcriptional sub-network that differentiates them from their circulating memory (TCM and TEM) counterparts. This raises the hypothesis that resident module is essential for orchestrating TRM differentiation and migration to their local niche and that positive/negative regulation of resident module may drive/suppress tissue residency