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T follicular helper cells in human efferent lymph retain lymphoid characteristics
Laura A. Vella, … , Michael R. Betts, E. John Wherry
Laura A. Vella, … , Michael R. Betts, E. John Wherry
Published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3185-3200. https://doi.org/10.1172/JCI125628.
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Research Article Immunology

T follicular helper cells in human efferent lymph retain lymphoid characteristics

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Abstract

T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1–bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.

Authors

Laura A. Vella, Marcus Buggert, Sasikanth Manne, Ramin S. Herati, Ismail Sayin, Leticia Kuri-Cervantes, Irene Bukh Brody, Kaitlin C. O’Boyle, Hagop Kaprielian, Josephine R. Giles, Son Nguyen, Alexander Muselman, Jack P. Antel, Amit Bar-Or, Matthew E. Johnson, David H. Canaday, Ali Naji, Vitaly V. Ganusov, Terri M. Laufer, Andrew D. Wells, Yoav Dori, Maxim G. Itkin, Michael R. Betts, E. John Wherry

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Figure 1

The thoracic duct carries Tfh-enriched lymphocytes to the blood, including a population of CXCR5BrPD-1Br Tfh.

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The thoracic duct carries Tfh-enriched lymphocytes to the blood, includi...
(A) Nonnaive CD4+ T cells are gated as CXCR5+PD-1+ Tfh (blue boxes) and CXCR5BrPD-1Br Tfh (red boxes) with frequency (percentage) in matching color. Human figures created with BioRender. (B) Tfh frequencies in blood (n = 17), TDL (n = 15), LNs (n = 10), and tonsil (n = 4). (C) Tfh frequencies in TDL and blood from donors with paired samples (n = 10). (D) Frequency of CXCR5BrPD-1Br Tfh in the indicated tissues. (E) Paired analysis of CXCR5BrPD-1Br frequencies in TDL and blood. (F) RM Tfh frequency in the indicated tissues and (G) in paired PBMCs and TDL samples (n = 4, 2 LNs included from each animal, an iliac node and a mesenteric node). (H) CXCR5BrPD-1Br frequencies in the indicated tissues from RM (n = 4) with (I) paired frequencies. Error is reported as SD. Paired 2-tailed t tests were performed for data shown in C, E, G, and I. ANOVA with Holm-Šídák post-test was performed on log-transformed data shown in B, D, F, and H. In D, 0 values were replaced with 0.00001 for log transformation. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
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