[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Clonal Vγ6+Vδ4+ T cells promote IL-17–mediated immunity against Staphylococcus aureus skin infection
Mark C. Marchitto, Carly A. Dillen, Haiyun Liu, Robert J. Miller, Nathan K. Archer, Roger V. Ortines, Martin P. Alphonse, Alina I. Marusina, Alexander A. Merleev, Yu Wang, Bret L. Pinsker, Angel S. Byrd, Isabelle D. Brown, Advaitaa Ravipati, Emily Zhang, Shuting S. Cai, Nathachit Limjunyawong, Xinzhong Dong, Michael R. Yeaman, Scott I. Simon, Wei Shen, Scott K. Durum, Rebecca L. O’Brien, Emanual Maverakis, and Lloyd S. Miller
PNAS first published May 14, 2019 / DOI: https://doi.org/10.1073/pnas.1818256116
Edited by Rino Rappuoli, GlaxoSmithKline, Siena, Italy, and approved April 18, 2019 (received for review October 31, 2018)
Staphylococcus aureus is the most common cause of skin infections and is becoming increasingly resistant to antibiotics. If immune-based therapies are to provide an alternative to antibiotics, a better understanding of immunity to S. aureus skin infections is crucial. During an S. aureus skin infection in mice, a clonal Vγ6+Vδ4+ T cell population expressing a single complementarity-determining 3 (CDR3) region encoded by canonical TRGV6 and TRDV4 sequences expanded in the skin-draining lymph nodes, trafficked to infected skin, and promoted IL-17–mediated immune clearance by inducing neutrophil recruitment, inflammatory cytokines, and host defense peptides. Together, identification of a clonal T cell population in immunity to S. aureus skin infections provides a specific response to target for future vaccines and immunotherapies.
T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1β, and TNF, and host defense peptides. RNA-seq for TRG and TRDsequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4. However, only TRGV6and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.
Staphylococcus aureus – IL-17 – T cells – neutrophils – skin
1 To whom correspondence may be addressed. Email: firstname.lastname@example.org.
Author contributions: M.C.M., C.A.D., H.L., N.K.A., M.P.A., A.I.M., A.A.M., A.S.B., N.L., X.D., M.R.Y., S.I.S., W.S., S.K.D., R.L.O., E.M., and L.S.M. designed research; M.C.M., C.A.D., H.L., R.J.M., N.K.A., R.V.O., M.P.A., A.I.M., A.A.M., Y.W., B.L.P., A.S.B., I.D.B., A.R., E.Z., S.S.C., N.L., and W.S. performed research; A.I.M., A.A.M., W.S., S.K.D., R.L.O., and E.M. contributed new reagents/analytic tools; M.C.M., C.A.D., H.L., R.J.M., N.K.A., R.V.O., M.P.A., A.I.M., A.A.M., Y.W., B.L.P., A.S.B., I.D.B., A.R., E.Z., S.S.C., N.L., X.D., M.R.Y., S.I.S., W.S., S.K.D., R.L.O., E.M., and L.S.M. analyzed data; and M.C.M., C.A.D., H.L., N.K.A., A.I.M., A.A.M., M.R.Y., S.I.S., S.K.D., R.L.O., E.M., and L.S.M. wrote the paper.
Conflict of interest statement: M.R.Y. is a cofounder of NovaDigm Therapeutics, which is developing novel vaccines and immunotherapeutics for infectious diseases, including S. aureus. L.S.M. has received grant support for work unrelated to the work reported in this manuscript from AstraZeneca, Pfizer, Regeneron Pharmaceuticals, Moderna Therapeutics, and Boehringer Ingelheim, is on the scientific advisory board for Integrated Biotherapeutics, and is a shareholder of Noveome Biotherapeutics, which are each developing vaccines and therapeutics against S. aureus and other pathogens.
This article is a PNAS Direct Submission.
Data deposition: The RNA-sequencing data reported in this paper have been deposited in the NCBI Sequence Read Archive (SRA) (accession no. SRP194263).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818256116/-/DCSupplemental.
Published under the PNAS license.
Keywords: Staphylococcus aureus.