IL-6 is a Key Factor in the Formation of Gut Tissue Resident Memory T Cells from Naïve T cells

Tissue resident memory CD4 ⁺ T cells (T _RM s) populate mucosal sites and play a critical role in local immune responses. Gut T _RM cells persist for extended periods in the gut mucosa where they rapidly respond to invading pathogens and provide long lasting protection. This study investigates the factors that mediate differentiation of naïve CD4 ⁺ T cells into cells presenting a gut T _RM phenotype. Naïve CD4 ⁺ T cells were cultured under conditions that mimicked mucosal environments. This included signaling through MAdCAM-1 in the presence of Retinoic Acid (RA) and TGF-β. This combination of stimuli primed naïve CD4 ⁺ T cells to adopt a T _RM phenotype. However, to fully differentiate into T _RM s an additional soluble factor provided by memory T cells was required. Our results identified IL-6 as a key factor that induces the expression of T _RM -associated markers, including CD69, CD103 and CCR5. This unique combination of stimuli promoted T _RM differentiation despite low level proliferation. T _RM differentiation was mediated through JAK/STAT signaling, and antagonists that target JAK/STAT pathways suppressed MAdCAM-1 mediated T _RM cell formation. Our findings revealed that MAdCAM-1 works together with TGF-β, RA and IL-6 in this process. Such information may aid in the design of next generation adjuvants and effective mucosal vaccines. Additionally, each of these factors may be targeted to treat excessive gut inflammation associated with conditions like inflammatory bowel disease. Overall, these findings provide new strategies aimed at modulating immune responses to invading pathogens and identify therapeutic approaches toward regulating gut inflammation.