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

Hans Kim, Amanda Chan, Sinmanus Vimopatranon, Alexandre Girard, Andrew Jiang, Samuel Wertz, Il-Young Hwang, John H Kehrl, Hana Schmeisser, Madelyn M Seemiller, Paolo Lusso, Dawei Huang, Danlan Wei, Livia R. Goes, Marcelo Soares, Elena Martinelli, James Arthos, Claudia Cicala
2025 · doi:10.1101/2025.06.23.660664
preprint OA: closed Public-Domain
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Abstract

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. Author Summary Immunologists and vaccinologists have long been interested in strategies aimed at boosting immune responses in mucosal tissues where pathogens are first encountered. Gut Tissue resident memory T cells (T RM s) play a central role in gut homeostasis and immunity. They provide a rapid long-lasting protection against pathogens. T RM s must target harmful pathogens and at the same time tolerate harmless commensal bacteria. This balance between immunity and tolerance in the complex environment of gut tissues is essential to the maintenance of gut homeostasis. In this study we have identified key factors present in the gut tissue milieu that are involved in T RM differentiation from naïve T cells. These findings point to new therapeutic approaches that can potentially target immune responses in gut tissues and may help in developing effective mucosal vaccines. Conversely, these factors may be targeted in excessive gut inflammation involved in conditions like inflammatory bowel disease (IBD). Graphical Abstract
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Abstract Tissue resident memory CD4+ T cells (TRMs) populate mucosal sites and play a critical role in local immune responses. Gut TRM 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 TRM 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 TRM phenotype. However, to fully differentiate into TRMs 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 TRM -associated markers, including CD69, CD103 and CCR5. This unique combination of stimuli promoted TRM differentiation despite low level proliferation. TRM differentiation was mediated through JAK/STAT signaling, and antagonists that target JAK/STAT pathways suppressed MAdCAM-1 mediated TRM 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. Author Summary Immunologists and vaccinologists have long been interested in strategies aimed at boosting immune responses in mucosal tissues where pathogens are first encountered. Gut Tissue resident memory T cells (TRMs) play a central role in gut homeostasis and immunity. They provide a rapid long-lasting protection against pathogens. TRMs must target harmful pathogens and at the same time tolerate harmless commensal bacteria. This balance between immunity and tolerance in the complex environment of gut tissues is essential to the maintenance of gut homeostasis. In this study we have identified key factors present in the gut tissue milieu that are involved in TRM differentiation from naïve T cells. These findings point to new therapeutic approaches that can potentially target immune responses in gut tissues and may help in developing effective mucosal vaccines. Conversely, these factors may be targeted in excessive gut inflammation involved in conditions like inflammatory bowel disease (IBD). Competing Interest Statement The authors have declared no competing interest.

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