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. 2009 May 11;206(5):1001-7.
doi: 10.1084/jem.20090313. Epub 2009 Apr 20.

V体育官网入口 - IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells

Irah L King  1 , Markus Mohrs
Affiliations

IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells

Irah L King et al. J Exp Med. .

Abstract

Interleukin (IL)-4 is the quintessential T helper type 2 (Th2) cytokine produced by CD4(+) T cells in response to helminth infection. IL-4 not only promotes the differentiation of Th2 cells but is also critical for immunoglobulin (Ig) G1 and IgE isotype-switched antibody responses VSports手机版. Despite the IL-4-mediated link between Th2 cells and B lymphocytes, the location of IL-4-producing T cells in the lymph nodes is currently unclear. Using IL-4 dual reporter mice, we examined the Th2 response and IL-4 production in the draining mesenteric lymph nodes during infection with the enteric nematode Heligmosomoides polygyrus. We show that although IL-4-competent Th2 cells are found throughout the B and T cell areas, IL-4-producing Th2 cells are restricted to the B cell follicles and associate with germinal centers. Consistent with their localization, IL-4 producers express high levels of CXCR5, ICOS, PD-1, IL-21, and BCL-6, a phenotype characteristic of T follicular helper (Tfh) cells. Although IL-4 was dispensable for the generation of Th2 and Tfh cells, its deletion resulted in defective B cell expansion and maturation. Our report reveals the compartmentalization of Th2 priming and IL-4 production in the lymph nodes during infection, and identifies Tfh cells as the dominant source of IL-4 in vivo. .

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Figures (V体育ios版)

Figure 1.
Figure 1.
huCD2+ IL-4–producing cells accumulate in B cell follicles and germinal centers during H. polygyrus infection. mesLNs from (A–C) 4get/KN2, (D–F) 4get, or (G and H) BALB/c mice at day 14 after infection with H. polygyrus. mesLNs in A–C are stained with CD4 (blue), huCD2 (red), and B220 (green; A and B) or PNA (green; C) for germinal center detection. F shows a huCD2 staining control for C. D, E, G, and H show cells expressing GFP (green), B220 (blue), and CD4 (red). The inset in D is an enlarged image of the area designated by the arrow. Each panel is representative of at least three separate experiments with three mice per group. Bar, 50 µm.
Figure 2.
Figure 2.
huCD2 marks T follicular cells in the reactive lymph nodes during helminth infection. (A) Gated CD4+ T cells from mesLNs of naive or H. polygyrus–infected 4get/KN2 mice were assessed for enhanced GFP (eGFP) and huCD2 expression. Numbers shown indicate cell frequency within the total CD4+ population. (B) CD4+ subset expression of various Tfh markers. Subsets are based on the gating in A. Shaded histograms represent GFP−huCD2− cells. GFP+huCD2− and GFP+huCD2+ cells are shown as dashed and continuous lines, respectively. (C) Real-time RT-PCR analysis of the T cell subsets shown in A. Data shown are normalized to GAPDH. (D) The frequency of Tfh cells in naive or infected 4get/KN2 mice based on CXCR5 and PD-1 expression. (E) huCD2 expression on the mesLN CXCR5+PD-1+ cells shown in C. (F) CXCR5 and PD-1 expression on huCD2+ cells from H. polygyrus–infected animals as shown in A (right). Data shown are representative of four separate experiments with three to five mice per group.
Figure 3.
Figure 3.
IL-4 producers are absent from the T cell zones during early H. polygyrus infection. mesLNs from (A) naive 4get/KN2 mice or at (B) day 3, (C and D) day 4, (E and F) day 5, and (G and H) day 7 after H. polygyrus infection. B220 (green), CD4 (blue), and hCD2 (red) stainings are shown. Each panel is representative of two separate experiments with four mice per group. Bar, 50 µm.
Figure 4.
Figure 4.
IL-4 is dispensable for Tfh cell generation. (A) mesLNs from 4get/KN2, 4get, and KN2/KN2 (IL-4–deficient) mice were harvested 14 d after H. polygyrus infection, and cells were stained for CXCR5 and PD-1 expression. Data shown are gated on CD4+ cells. Numbers represent the frequency of the boxed population within the CD4+ population. (B) huCD2 expression on CXCR5+PD-1+ cells (open histograms) as shown in A. CXCR5−PD-1− cells (shaded histograms) are shown for comparison. (C) 4get/KN2 or KN2/KN2 mesLNs from H. polygyrus–infected animals stained with B220 (green), CD4 (blue), and huCD2 (red). Results shown are representative of two separate experiments with four mice per group. Bars, 50 µm.
Figure 5.
Figure 5.
B cell expansion and maturation critically depend on IL-4 signaling. mesLNs from 4get/KN2 or IL-4Rα−/−mice were harvested from naive animals 1 or 2 wk after H. polygyrus infection, and the total number of CD4+GFP+ (A) cells and CD19+ (B) cells was calculated. Error bars represent the mean ± SEM. (C) mesLN CD19+ cells stained for the indicated markers at 2 wk after infection. Open histograms represent cells from H. polygyrus–infected 4get/KN2 mice. IL-4Rα−/− B cells (shaded) are shown for comparison. (D and E) mesLN CD19+ cells from H. polygyrus–infected 4get/KN2 and IL-4Rα−/− mice stained for PNA and Fas (D) or IgD and IgG1 (E). Numbers represent the frequency of the boxed population within the CD19+ population. All plots shown are representative of at least three mice per group from two or more individual experiments.
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