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Tc17, a Unique Subset of CD8 T Cells That Can Protect against Lethal Influenza Challenge¹

Trudeau Institute, Saranac Lake, NY 12983

We show here that IL-17-secreting CD4 T (Th)17 and CD8 T (Tc)17 effector cells are found in the lung following primary challenge with influenza A and that blocking Ab to IL-17 increases weight loss and reduces survival. Tc17 effectors can be generated in vitro using naive CD8 T cells from OT-I TCR-transgenic mice. T cell numbers expand 20-fold and a majority secretes IL-17, but little IFN-. Many of the IL-17-secreting cells also secrete TNF and some secrete IL-2. Tc17 are negative for granzyme B, perforin message, and cytolytic activity, in contrast to Tc1 effectors. Tc17 populations express message for orphan nuclear receptor t and FoxP3, but are negative for T-bet and GATA-3 transcription factors. The FoxP3-positive, IL-17-secreting and IFN--secreting cells represent three separate populations. The IFN--, granzyme B-, FoxP3-positive cells and cells positive for IL-22 come mainly from memory cells and decrease in number when generated from CD44^low rather than unselected CD8 T cells. Cells of this unique subset of CD8 effector T cells expand greatly after transfer to naive recipients following challenge and can protect them against lethal influenza infection. Tc17 protection is accompanied by greater neutrophil influx into the lung than in Tc1-injected mice, and the protection afforded by Tc17 effectors is less perforin but more IFN- dependent, implying that different mechanisms are involved.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant P01AI46530 and by the Trudeau Institute.

² Address correspondence and reprint requests to Dr. Richard W. Dutton and Dr. Hiromasa Hamada, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail addresses: dickdutton{at}gmail.com and hhamada{at}trudeauinstitute.org

³ Abbreviations used in this paper: RA, retinoic acid; BAL, bronchoalveolar lavage; DXS, dextran sulfate; EID₅₀, 50% egg infective dose; ILN, inguinal lymph node; i.n., intranasal; LCMV, lymphocytic choriomeningitis virus; MedLN, mediastinal lymph node; NP, nucleoprotein; RORt, orphan nuclear receptor t; Tc, CD8 T cytotoxic; TCID₅₀, 50% tissue culture infective dose; nTc17, naive Tc17.

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