Editors' ChoiceImmunology

Self-Destructive But Self-Controlled

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Science Translational Medicine  29 Feb 2012:
Vol. 4, Issue 123, pp. 123ec34
DOI: 10.1126/scitranslmed.3003898

Seventeen is usually about hanging out where the action is. Not so with T helper 17 (CD4+ TH17) cells. Although part of the in-crowd for the past several years owing to their central role in the pathogenesis of human autoimmune and chronic inflammatory diseases, TH17 cells appear to avoid the spotlight and exist only in low amounts at inflammatory sites. In a series of elegant and well-controlled experiments using human T cells, Santarlasci et al. tackled this curiosity by demonstrating that relative to Th1 cells—other effector cells specialized to produce interferon-γ during viral infections and cancer—human TH17 cells exhibit a lower ability both to proliferate in response to T cell receptor stimulation and to produce interleukin-2 (IL-2), a vital T cell growth factor.

So named for their key product, IL-17, CD4+ TH17 cells have been linked to Crohns disease, multiple sclerosis, rheumatoid arthritis, psoriasis, allergy, and asthma. The authors uncovered a mechanism for the cells’ restricted ability to make IL-2 and multiply. Human CD4+ TH17 cells isolated from circulating blood were shown to synthesize their signature cytokine, IL-17, while bypassing normal T cell receptor signaling. First, the authors observed enhanced expression of IL-4–induced gene 1 (IL4I1) mRNA in human TH17 cells relative to TH1 cells. TH17 cells also displayed abnormal expression of the T cell receptor–associated signaling molecule CD3ζ along with impaired activity in the IL-2 production pathway. Blocking IL41R expression largely restored the IL-2 defect and T cell proliferation, revealing a link between IL41R expression, inhibition of T cell division, and IL-2 production. Expression of IL4I1 mRNA occurred early in development, as TH17 cell precursors from human newborn thymus and umbilical-cord blood expressed high amounts of IL4I1 mRNA.

In the human TH17 cells, expression of the gene that encodes the retinoic acid–related orphan receptor (RORC)—the master transcriptional regulator of TH17 cell development from thymocytes—was shown to enhance expression of IL4I1 and the gene that encodes the T cell coreceptor protein CD28, which was produced in large amounts. Although conventional CD3–T cell receptor signaling was impaired, TH17 cells produced IL-17 via CD28 signaling alone. TH17 synovial cells from patients with juvenile idiopathic arthritis also expressed high levels of CD28 and IL4I1 mRNA and displayed impaired proliferation.

These findings reveal that the rarity of human TH17 cells in the inflamed tissues of patients with autoimmune diseases results from a form of self-control, a trait not often associated with being 17. RORC-dependent mechanisms limit the cells’ expansion and potential further damage to self tissues. Current biological therapies for many TH17-associated autoimmune diseases focus on blocking inflammatory cytokines [such as tumor necrosis factor–α (TNFα) and IL-17]. These results may offer a further rationale for treating patients who do not respond to TNFα inhibition with an agent that blocks the CD28 receptor signaling pathway or that promotes IL4I1 expression and thus greater self control. Further work is needed to understand what drives the difference between ruly and unruly seventeens in healthy patients and those with autoimmune and inflammatory diseases.

V. Santarlasci et al., Rarity of human T helper 17 cells is due to retinoic acid orphan receptor–dependent mechanisms that limit their expansion. Immunity 36, 201–214 (2012). [Abstract]

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