Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 8, Pages 3185-3200Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI125628
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Funding
- Pediatric Infectious Diseases Society Fellowship Award
- National Center for Advancing Translational Sciences of the NIH [KL2TR001879]
- Mentored Research Scholar Award from the Penn Center for AIDS Research (CFAR), an NIH [P30 AI 045008]
- Mentored Clinical Scientist Career Development Award from the National Institute of Allergy and Infectious Diseases [K08AI136660]
- Swedish Research Council [53720146829]
- Karolinska Institute
- Novartis Canada
- United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program [I01 BX002644]
- National Institute of Allergy and Infectious Diseases [RO1 AI23539]
- NIH [GM118553, R01 AI076066, R01 118694, AI105343, AI112521, AI082630, AI117950]
- Parker Institute for Cancer Immunotherapy
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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 (CXCR5(Br)PD-1(Br)) Tfh population in thoracic duct lymph (TDL). These CXCR5(Br)PD-1(Br) TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5(Br)PD-1(Br) 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 CXCR5(Br)PD-1(Br) 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.
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