American Association of Immunologists, The Journal of Immunology, 1_Supplement(206), p. 98.41-98.41, 2021
DOI: 10.4049/jimmunol.206.supp.98.41
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Abstract Although the loss of naive CD8 T cells is a hallmark of immune aging, naïve CD4 T cells appear to be more resilient, demonstrating less numerical loss and fewer transcriptional and epigenetics changes with age. That said, naïve CD4 T cells still display altered antigen-specific responses and subset polarization with age, implying that although numerically robust, the composition of the naïve CD4 T cell population may differ with age. Thus, we examined the compositional heterogeneity of naïve CD4 T cell compartment using mass cytometry during human aging. We found that a unique CD45RAhigh population was lost with age, converting to a CD45RA+/low population in older individuals. In young adults, CD45RAhigh naïve T cells were found highly enriched in the lymph nodes (LN). To determine the role of the LN microenvironment in the maintenance of CD45RAhigh population, we developed bioengineered human LN-like organoids that actively maintained this cell type, requiring both fibroblastic reticular cells (FRCs) and a 3D structure. Notably, within these LN-like organoids, CD45RA+/low naïve CD4 T cells from older individuals were able to convert back to a CD45RAhigh phenotype, implying cell extrinsic influences mediate naïve T cell aging. However, neither aging nor cellular senescence of FRCs caused the conversion of naive T cells to an aged CD45RA+/low phenotype. Together, these data suggest that naïve T cell aging is not directly mediated by intrinsic age-related defects in stromal FRCs but instead may be linked with structural changes within the LN microenvironment of older individuals.