Lymph Nodes and Peyer’s Patches Harbor Resident CD4+ T Cells That Accumulate After Prolonged Antigen Exposure

CD4⁺ T cells can acquire various migratory properties during immune responses to provide enhanced immuno-surveillance and protection. However, the comprehensive analysis of these migratory properties has been difficult due to highly dynamic nature of T cell circulation. We developed two independent long-term in vivo cell tracking methods to analyze the migration of effector/memory CD4⁺ T cells. We identified a resident population of effector/memory CD4⁺ T cells that stays in lymph nodes and Peyer’s patches (PPs) without circulation or proliferation. Resident CD4⁺ T cells constitute up to 50% of all effector/memory cells, including, but not limited to, follicular helper T cells. This functionally heterogeneous population of resident cells expresses low levels of egress-promoting sphingosine-1-phosphate receptor 1 (S1pr1) and possesses a distinct TCR repertoire. Furthermore, resident cells constituted a significant portion of all CD4⁺ T cells in PPs and accumulated in these organs after continuous oral antigen exposure. Our results define a previously unrecognized population of effector/memory CD4⁺ T cells in lymphoid tissues which might perform similar functions as non-lymphoid tissue-resident memory T cells.