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. 2008 Jul 7;205(7):1551-7.
doi: 10.1084/jem.20080218.

Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3

Cindy S Ma  1 , Gary Y J Chew, Nicholas Simpson, Archana Priyadarshi, Melanie Wong, Bodo Grimbacher, David A Fulcher, Stuart G Tangye, Matthew C Cook
Affiliations

Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3

Cindy S Ma et al. J Exp Med. .

Abstract

Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.

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Figures

Figure 1.
Figure 1.
HIES patients have a defect in the generation of IL-17–producing CD4+ T cells in vivo. Intracellular expression of IL-17A and IL-2 in purified CD4+ T cells from a healthy donor (A) and a HIES patient (B) activated for 5 d (see Materials and methods). (C) The frequency of IL-17A+ cells, determined by intracellular cytokine expression, and (D) IL-17A secretion by CD4+ T cells from five healthy donors and five HIES patients that had been stimulated with anti-CD3 mAb, anti-CD28 mAb, and IL-2 for 4–5 d, as determined by ELISA. Each symbol represents the value from an individual donor or patient, and the line represents the mean. (E) Time course of IL-17A secretion by CD4+ T cells isolated from a normal donor and HIES patient. Similar results were obtained when CD4+ T cells from all HIES patients were examined over a culture period that continued for up to 11 d. (F and G) Expression of IL-22 mRNA (relative to housekeeping genes; F) and secreted protein (G) by normal and HIES CD4+ T cells was determined after 2 and 5 d, respectively, of stimulation with CD3/CD28/IL-2. *, P < 0.05; **, P < 0.01.
Figure 2.
Figure 2.
Deficiency of RORγt mRNA in HIES patients. (A) RORγt mRNA expression in CD4+ cells activated for 2 d with CD3/CD28/IL-2 in five HIES patients and five normal controls. (B) RORγt mRNA expression after 2 d of culture is proportional to the number of Th17 cells as determined by intracellular cytokine expression after 4–5 d.
Figure 3.
Figure 3.
CD4+ T cells from HIES patients undergo normal proliferation and differentiation into Th1-, Th2-, T reg–, and TFH-type effector cells. (A) CFSE profiles of normal (outline black histogram) and HIES (solid red histogram) CD4+ T cells after stimulation with CD3/CD28 mAb and IL-2 for 5 d. (B) Intracellular expression of IFN-γ and IL-2 in CD4+ T cells purified from normal donors and HIES patients after activation for 4–5 d with CD3/CD28/IL-2. The FACS plots in B are representative of one normal control and one HIES patient. (C and D) Frequency of CD4+ T cells from normal controls and HIES patients that expressed IL-2 (C) or IFN-γ (D). (E–I) Secretion of IFN-γ (E), TNF-α (F), IL-4 (G), IL-10 (H), and IL-13 (I) by normal and HIES CD4+ T cells stimulated with anti-CD3/CD28 mAb and IL-2 for 5 d. (J and K) CD4+ T cells were labeled with either (J) CD25 and CD127 to identify T reg cells (CD25hiCD127lo) or (K) CXCR5 to identify TFH cells, as indicated by the gated populations. The values represent the frequency of gated cells and are from one healthy donor and one HIES patient and are representative of at least four patient and control samples. (L) PBMCs were labeled with anti-CD4 and CCR6 mAb, and the frequency of CD4+ CCR6+ cells in healthy donors and HIES patients was enumerated. For all graphs (E–I and L), each symbol represents the value from an individual donor or patient, and the line represents the mean. *, P < 0.05; **, P < 0.01; ns, not significant.
Figure 4.
Figure 4.
Naive CD4+ T cells from HIES patients fail to differentiate to the Th17 lineage in vitro in response to the STAT3-activating cytokines IL-6 and IL-23. Naive CD4+ T cells isolated from a normal donor (▪, □) and a HIES patient (▴, ▵) were cultured with anti-CD2, anti-CD3, and anti-CD28 mAb-coated beads either alone (CD3) or in the presence of IL-1β plus IL-6 (IL-1β+IL-6), IL-23 (IL-23), or all three cytokines (IL-1β +IL-6+IL-23). The cells were harvested after 5 d and then recultured under the same conditions for another two rounds of stimulation. (A) IL-17A secretion was determined after either 3 d (▪, ▴; total time of culture, 12 d) or 6 d of the third round of restimulation (□, ▵; total time of culture, 15 d). (B) Expression of RORγt mRNA in cells stimulated for 5 d (▪, ▴) or 15 d (□, ▵) was determined by quantitative PCR.
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