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 one of the key factors 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.
Kim et al. (Mon,) studied this question.