Human lymph nodes maintain TCF-1hi memory T cells with high functional potential and clonal diversity throughout life 1

摘要

Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. Here, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors, and identify a subset of memory CD8⁺T cells in LN which maintain a distinct differentiation and functional profile compared to memory CD8⁺T cells in blood, spleen, bone marrow (BM), and lungs. Whole transcriptome and high dimensional CyTOF profiling reveals that LN memory CD8⁺T cells express signatures of quiescence and self-renewal compared to corresponding populations in blood, spleen, BM and lung. LN memory T cells exhibit a distinct transcriptional signature including expression of stem cell-associated transcription factors TCF-1, LEF-1, T-follicular helper cell markers CXCR5, and CXCR4, and reduced expression of effector molecules. LN memory T cells display high homology to a subset of mouse CD8⁺T cells identified in chronic infection models which responds to checkpoint blockade immunotherapy. Functionally, human LN memory T cells exhibit increased proliferation to T cell receptor (TCR)-mediated stimulation and maintain higher TCR clonal diversity compared to memory T cells from blood and other sites. These findings establish human LN as reservoirs for memory T cells with high capacities for expansion and diverse recognition and important targets for immunotherapies.