Identification of novel markers for mouse CD4+ T follicular helper cells

Smita S. Iyer, Donald R. Latner, Michael J. Zilliox, Megan Mccausland, Rama S. Akondy, Pablo Penaloza-Macmaster, Jeffrey Scott Hale, Lilin Ye, Ata Ur Rasheed Mohammed, Tomoyuki Yamaguchi, Shimon Sakaguchi, Rama R. Amara, Rafi Ahmed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


CD4+ T follicular helper (TFH) cells are central for generation of long-term B-cell immunity. A defining phenotypic attribute of TFH cells is the expression of the chemokine R CXCR5, and TFH cells are typically identified by co-expression of CXCR5 together with other markers such as PD-1, ICOS, and Bcl-6. Herein, we report high-level expression of the nutrient transporter folate R 4 (FR4) on TFH cells in acute viral infection. Distinct from the expression profile of conventional TFH markers, FR4 was highly expressed by naive CD4+ T cells, was downregulated after activation and subsequently re-expressed on TFH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory TFH cells. Comparative gene expression profiling of FR4hi versus FR4lo Ag-specific CD4+ effector T cells revealed a molecular signature consistent with TFH and TH1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto-enzyme CD73, were enriched in TFH cells compared with TH1 cells, and phenotypic analysis confirmed expression of CD73 on TFH cells. As there is now considerable interest in developing vaccines that would induce optimal TFH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of TFH cells following vaccination and infection.

Original languageEnglish (US)
Pages (from-to)3219-3232
Number of pages14
JournalEuropean Journal of Immunology
Issue number12
StatePublished - Dec 2013


  • B cells
  • CD73
  • Folate R 4
  • Viral infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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