Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells

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Abstract

Interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) have been characterized in mice as a distinct subset of effector cells, but their identity and properties in humans remain elusive. We report here that expression of CCR6 and CCR4 together identified human memory CD4+ T cells selectively producing IL-17 and expressing mRNA encoding the human ortholog of mouse RORγt, a transcription factor, whereas CCR6 and CXCR3 identified TH1 cells producing interferon-γ and T helper cells producing both interferon-γ and IL-17. Memory T cells specific for Candida albicans were present mainly in the CCR6+CCR4+ TH-17 subset, whereas memory T cells specific for Mycobacterium tuberculosis were present in CCR6+CXCR3+ T helper type 1 subset. The elicitation of IL-17 responses correlated with the capacity of C. albicans hyphae to stimulate antigen-presenting cells for the priming of TH-17 responses in vitro and for the production of IL-23 but not IL-12. Our results demonstrate that human TH-17 cells have distinct migratory capacity and antigenic specificities and establish a link between microbial products, T helper cell differentiation and homing in response to fungal antigens.

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Figure 1: IL-17-producing CD4+ T cells express CCR6 in both the peripheral blood of healthy donors and in the synovial tissues of patients with juvenile idiopathic arthritis.
Figure 2: CCR4 and CXCR3 distinguish two stable subsets of IL-17-producing T cells in the CCR6+ compartment.
Figure 3: Constitutive and inducible expression of RORC, TBX21 and GATA3 in memory T cell subsets.
Figure 4: CCR6 is upregulated in differentiating TH-17 cells.
Figure 5: C.albicans–specific memory T cells are skewed toward TH-17.
Figure 6: Hyphae of C.albicans prime TH-17 responses and induce IL-23 but not IL-12 release.

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Acknowledgements

We thank M. Messi for help with initial experiments, and M. Manz and M. Uguccioni for critical reading and comments. Anti-α4β7 (Act1) was from C.R. Mackay (The Garvan institute). Supported by the Swiss National Science Foundation (31-101962 to F.S. and 31-112678 to A.L.), the European Commission FP6 Programme (LSHP-CT-2003-503240 (Mucosal Vaccines for Poverty-Related Diseases); LSB-CT-2005-518167 (Innovative Chemokine-Based Therapeutic Strategies for Autoimmunity and Chronic Inflammation)), the National Institutes of Health (U19 AI057266-01) and the Helmut Horten Foundation (for The Institute for Research in Biomedicine).

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Correspondence to Federica Sallusto or Giorgio Napolitani.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

IL-17-producing T cells do not segregate with the expression of CLA or α4β7. (PDF 36 kb)

Supplementary Fig. 2

Phenotypic identification and sorting gates of memory CD4+ T cells. (PDF 35 kb)

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